WO2024061202A1 - Acide ribonucléique double brin pour l'inhibition de l'expression du gène hmgb1, et modificateur, conjugué et son utilisation - Google Patents

Acide ribonucléique double brin pour l'inhibition de l'expression du gène hmgb1, et modificateur, conjugué et son utilisation Download PDF

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Publication number
WO2024061202A1
WO2024061202A1 PCT/CN2023/119654 CN2023119654W WO2024061202A1 WO 2024061202 A1 WO2024061202 A1 WO 2024061202A1 CN 2023119654 W CN2023119654 W CN 2023119654W WO 2024061202 A1 WO2024061202 A1 WO 2024061202A1
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seq
nucleotide sequence
sequence shown
strand includes
antisense strand
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Chinese (zh)
Inventor
王岩
黄河
王书成
林国良
产运霞
耿玉先
汪小君
荣梅
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Beijing Foyou Pharmaceutical Co Ltd
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Beijing Winsunny Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present disclosure belongs to the field of biomedicine. Specifically, the present disclosure relates to a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, a pharmaceutical composition and use for inhibiting HMGB1 gene expression, and a method for inhibiting HMGB1 gene expression in cells.
  • High mobility group box-1 (HMGB1) is a highly conserved nuclear protein that is widely distributed in mammalian cells.
  • HMGB1 High mobility group box-1
  • activated monocytes, macrophages or necrotic cells can release large amounts of HMGB1, which can induce the production of pro-inflammatory factors such as TNF-alpha and IL-6 through receptors such as TLR4.
  • pro-inflammatory factors such as TNF-alpha and IL-6 through receptors such as TLR4.
  • TLR4 receptors such as TLR4.
  • insulin resistance increases the concentration of free fatty acids in the blood and leads to massive lipid deposition in the liver, which damages liver macrophages.
  • the damaged liver macrophages release large amounts of HMGB1 and other cytokines and chemokines. .
  • liver macrophages will also recruit and activate a large number of bone marrow-derived macrophages into the liver. These activated bone marrow-derived macrophages will release more HMGB1 and chemokines. , and recruit more macrophages into the liver, forming a vicious cycle.
  • Activated macrophages not only release cytokines that promote disease progression, but also express markers of macrophage activation on their surface, such as CD163 and mannose receptors.
  • HMGB1 As an important inflammatory factor, HMGB1 is not only involved in late-stage inflammatory responses in many diseases such as sepsis, arthritis, colitis, and acute lung injury, but is also involved in tumors (such as colorectal cancer, gastric cancer, myelodysplastic syndrome, It also plays an important role in the evolution of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma, etc.). During the evolution and progression of malignant tumors, HMGBl can inhibit cell apoptosis and activate proliferation. Mechanisms such as signaling, promoting extracellular matrix degradation, exerting the effect of chemokines, increasing cell movement, inducing tumor angiogenesis, etc., ultimately lead to malignant transformation and uncontrollable growth of tumors, and promote tumor progression.
  • tumors such as colorectal cancer, gastric cancer, myelodysplastic syndrome, It also plays an important role in the evolution of acute myeloid
  • the present invention aims to provide double-stranded ribonucleic acid, double-stranded ribonucleic acid modifications, double-stranded ribonucleic acid conjugates, pharmaceutical compositions and uses for inhibiting HMGB1 gene expression, as well as methods for inhibiting intracellular HMGB1 gene expression, It can affect the RNA-induced silencing complex (RISC)-mediated cleavage of the RNA transcript of the HMGB1 gene, thereby inhibiting the expression of the HMGB1 gene and achieving the treatment of hepatobiliary diseases such as non-alcoholic steatohepatitis (NASH hepatitis); sepsis arthritis; colitis; acute lung injury; and cancers such as colorectal cancer, gastric cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma, and diseases such as atherosclerosis.
  • RISC
  • HMGB1 inhibitors need to be developed for the treatment of non-alcoholic steatohepatitis, sepsis, arthritis, colitis, acute lung injury, colorectal cancer, gastric cancer, HMGB1-related diseases including myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma, atherosclerosis and other diseases.
  • the present disclosure aims to provide a series of double-stranded ribonucleic acids, double-stranded ribonucleic acid modifications, double-stranded ribonucleic acid conjugates and pharmaceutical compositions for inhibiting HMGB1 gene expression, which can inhibit HMGB1 gene expression and have utility in clinical disease treatment. important application prospects.
  • a double-stranded ribonucleic acid the double-stranded ribonucleic acid includes a sense strand and an antisense strand, the sense strand is complementary and/or substantially reverse complementary to the antisense strand to form the double-stranded ribonucleic acid the double-stranded region;
  • the sense strand includes a sequence that differs from at least 15 consecutive nucleotides in the target sequence by no more than 3 nucleotides.
  • Sequence A the antisense strand comprising sequence B that differs by no more than 3 nucleotides from the reverse complement of at least 15 consecutive nucleotides in the target sequence;
  • the target sequence is selected from the nucleotide sequence shown in any one of SEQ ID NO: 1-16 and SEQ ID NO: 560-567.
  • the sense strand includes at least 15 consecutive nucleotides in the nucleotide sequence shown in any one of SEQ ID NO:17 ⁇ 68, SEQ ID NO:560, SEQ ID NO:562-569
  • Sequence A consisting of, the antisense strand includes at least 15 consecutive nucleotides in the nucleotide sequence shown in any one of SEQ ID NO:17 ⁇ 68, SEQ ID NO:560, SEQ ID NO:562-569
  • the acid sequence consists of the reverse complement of sequence B.
  • [3] The double-stranded ribonucleic acid according to [1] or [2], wherein the sense strand consists of 15-28 nucleotides, preferably 19-25 nucleotides, more preferably 19-23 nucleotides nucleotides, more preferably 19, 21 or 23 nucleotides.
  • sequence consisting of 15-28 consecutive nucleotides in the nucleotide sequence shown in the item is preferably 19-25 consecutive nucleotides, and more preferably 19-23 consecutive nucleotides, more preferably 19, 21 or 23 nucleotides.
  • [5] The double-stranded ribonucleic acid according to any one of [1] to [4], wherein the antisense strand consists of 15-28 nucleotides, preferably 19-25 nucleotides, more preferably 19-23 nucleotides, more preferably 19, 21 or 23 nucleotides.
  • [6] The double-stranded ribonucleic acid according to [5], wherein the nucleotide sequence of the antisense strand is the same as SEQ ID NO: 17-68, SEQ ID NO: 560, SEQ ID NO: 562-569
  • the reverse complementary sequence of the sequence consisting of 15-28 consecutive nucleotides in the nucleotide sequence shown in any item is compared to the sequence B which differs by no more than 1 nucleotide, preferably 19-25 consecutive nucleotides. acid, more preferably 19-23 consecutive nucleotides, more preferably 19, 21 or 23 nucleotides.
  • [7] The double-stranded ribonucleic acid according to any one of [1]-[6], wherein the length of the double-stranded region is 15-25 nucleotides, preferably 19-23 nucleotides, more Preferred are 19-21 nucleotides, more preferably 19, 21 or 23 nucleotides.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the sense strand has 1-2 protruding nucleotides extending out of the double-stranded region, and the antisense strand is complementary to the double-stranded region.
  • the 3' end of the chain forms a blunt end; or,
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the antisense strand has 1-2 protruding nucleotides extending out of the double-stranded region, and the sense strand The 3' end of the chain forms a blunt end; or,
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand each have 1-2 protruding cores extending out of the double-stranded region. glycoside; or,
  • the sense strand and the antisense strand complement each other to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:69, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:179;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:70, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:180;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:71, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:181;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:72, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:182;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:73, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:183;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:74
  • the antisense strand includes the nucleotide sequence shown in SEQ ID NO:74
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:75
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:185;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:76, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:186;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:77, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:187;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:78, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:188;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:79, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:189;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:80, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:190;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:81, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:191;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:82, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:192;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:83, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:193;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:84, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:194;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:85, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:195;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:86, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:196;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:87, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:197;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:88, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:198;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:89, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:199;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:90, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:200;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:91, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:201;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:92, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:202;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:93, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:203;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:94, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:204;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:95, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:205;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:96, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:206;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:97, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:207;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:98, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:208;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:99, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:209;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:100, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:210;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:101, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:211;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:102, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:212;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 103, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 213;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:104, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:214;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:105, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:215;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:106, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:216;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:107, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:217;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:108, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:218;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:109, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:219;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 110, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 220;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:111, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:221;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 112, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 222;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO: 113, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 223;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:114, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:224;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:115, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:225;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:116, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:226;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO: 117, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 227;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:118, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:228;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:119, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:119 The nucleotide sequence shown in NO:229;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:120, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:230;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:121, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:231;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:122, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:232;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:123, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:233;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 124, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 234;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:125, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:235;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:126, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:236;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:127, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:237;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:128, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:238;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:129, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:239;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:130, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:240;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:131, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:241;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 132, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 242;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 133, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 243;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:134, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:244;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:135, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:245;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:136, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:246;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:137, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:247;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:138, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:248;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:139, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:249;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:140, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:250;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:141, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:251;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:142, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:252;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:143, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:253;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:144, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:254;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:145, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:255;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 146, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 256;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:147, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:257;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 148, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 258;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:149, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:259;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:150, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:260;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:151, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:261;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:152, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:262;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 153, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 263;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:154, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:264;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:155, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:265;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:156, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:266;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:157, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:267;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:158, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:268;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:159, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:269;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:160, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:270;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:161, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:271;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:162, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:272;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 163, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 273;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 164, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: The nucleotide sequence shown in NO:274;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:165, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:275;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:166, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:276;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:167, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:277;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:168, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:278;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:169, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:279;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 170
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 280;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 171
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 281;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:172, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:282;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:173, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:174, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:284;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 175, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 285;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:176, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:286;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:177, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:287;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:178, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:288;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:289, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:299;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 290, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 300;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:291, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:301;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:292, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:302;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 293, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 303;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:294, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:304;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 295, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 305;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:296, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:306;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:297, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:307;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:298, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:308;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:376, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:412;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 377, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 413;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:378, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:414;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:379, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:415;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:380, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:416;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:381, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:417;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:382, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:418;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:383, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:419;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 384, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 420;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:385, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:421;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 386, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 422;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:387, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:423;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:388, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:424;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:389, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:425;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:390, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:426;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:391, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:427;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 392, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 428;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:393, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:429;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:394, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:430;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:395, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:431;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:396, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:396 The nucleotide sequence shown in NO:432;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:397, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:433;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:398, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:434;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:399, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:435;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:400, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:436;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:401, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:437;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:402, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:438;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:403, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:439;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:404, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:440;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:405, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:441;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:406, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:442;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:407, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:443;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:408, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:444;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:409, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:445;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:410, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:446;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:411, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:447;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:570, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:603;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:571, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:604;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:572, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:605;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:573, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:606;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:574, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:607;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:575, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:608;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:576, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:609;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:577, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:610;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:578, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:611;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:579, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:612;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:580, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:613;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:581, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:614;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:582, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:615;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:583, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:616;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:584, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:617;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:585, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:618;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:586, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:619;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:587, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:620;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:588, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:621;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:589, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:622;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:590, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:623;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:591, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:624;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:592, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:625;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:593, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:626;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:594, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:627;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:595, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:628;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:596, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:629;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:597, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:630;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:598, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:631;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:599
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:599
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:600, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:633;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:601, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:634;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:602, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:635;
  • the sense strand and the antisense strand are selected from the following combinations:
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:75, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:185;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:98, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:208;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:107, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:217;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 117, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 227;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:123, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:233;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:130, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:240;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:377, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:413;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:378, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:414;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:379, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:415;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:407, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:443.
  • each nucleotide in the sense strand is independently a modified nucleotide or an unmodified nucleotide.
  • each nucleotide in the antisense strand is independently a modified nucleotide or an unmodified nucleotide.
  • a modified double-stranded ribonucleic acid which is a modified double-stranded ribonucleic acid as described in any one of [1] to [14], and the modified double-stranded ribonucleic acid contains at least one of the following Chemical modification:
  • sequence A in the sense strand of the double-stranded ribonucleic acid is connected to sequence D consisting of 1-2 nucleotides, preferably a sequence consisting of 1-2 thymidine deoxyribonucleotides D; and/or, the 3' end of sequence B in the antisense strand of the double-stranded ribonucleic acid is connected to sequence E consisting of 1-2 nucleotides, preferably 1-2 thymidine deoxyribonucleotides Sequence E consisting of; and/or sequence A' is formed after excluding 1-2 nucleotides from the 3' end of sequence A in the sense strand of the double-stranded ribonucleic acid;
  • the sense strand and antisense strand of the double-stranded ribonucleic acid modification are selected from the following sequence combinations:
  • nucleotide sequence of the sense strand is the sequence shown in sequence A, and the nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A connected to sequence D, and the nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A connected to sequence D
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A'
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A’
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E.
  • [16] The double-stranded ribonucleic acid modification according to [15], wherein the modification of the nucleotide is selected from the group consisting of 2'-fluoro modification, 2'-alkoxy modification, and 2'-substituted alkoxy. base modification, 2'-alkyl modification, 2'-substituted alkyl modification, 2'-deoxy modification, nucleotide derivative modification or a combination of any two or more thereof.
  • nucleotide derivative in the nucleotide derivative modification is selected from the group consisting of isonucleotides, LNA, ENA, and cET , UNA or GNA.
  • the sense strand contains phosphorothioate diester bonds at the positions shown below:
  • the ribonucleotides at positions 2, 6, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides,
  • the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides;
  • the ribonucleotides at positions 2, 6, 8, 9, 14 and 16 in the antisense strand are 2'- F-modified ribonucleotides, the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides;
  • the ribonucleotides at positions 2, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides, and the antisense strand
  • the ribonucleotide at position 6 in the chain is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense chain are ribonucleotides modified by 2'-O-CH 3 acid;
  • the ribonucleotides at positions 2, 6, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides
  • the ribonucleotide at position 7 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense strand are modified with 2'-O-CH 3 of ribonucleotides.
  • N 1 -N 23 are independently selected from ribonucleotides whose bases are A, U, C or G,
  • T stands for deoxyribonucleotide whose base is thymine.
  • the lowercase letter m indicates that the ribonucleotide adjacent to the right side of the letter m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is a 2’-F modified ribonucleotide.
  • N 1 -N 23 are independently selected from ribonucleotides whose bases are A, U, C or G,
  • T stands for deoxyribonucleotide whose base is thymine.
  • the lowercase letter m indicates that the ribonucleotide adjacent to the right side of the letter m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is a 2’-F modified ribonucleotide.
  • P1 means that the nucleotide adjacent to the right of the letter is a 5'-phosphate nucleotide.
  • -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond
  • GNA indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified by GNA.
  • the double-stranded ribonucleic acid modified substance according to any one of [15] to [26], wherein the double-stranded ribonucleic acid modified substance is an siRNA modified substance for inhibiting HMGB1 gene expression.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:309, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:343;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:310, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:343;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:311, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:344;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:312, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:345;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 313, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 345;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:314, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:346;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:315, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:347;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:316, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:347;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:317, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:348;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:318, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:349;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:319, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:349;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:320, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:350;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:321
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:350;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:322, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:351;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 323, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 351;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:324, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:352;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:325, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:353;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 326, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 353;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:327, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:354;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:328, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:355;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:356;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:330, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:356;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:331, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:357;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:358;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:333, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:358;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 334, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 359;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:335, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:359;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:336 The nucleotide sequence shown in NO:360;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 337, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 360;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:338, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:361;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 339, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 361;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:340, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:362;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:341, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:363;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:342, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:363;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:448, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:471;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:449, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:472;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:449, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:473;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:449, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:474;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:450, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:475;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:450, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:476;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:450, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:477;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:450, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:478;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:451, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:479;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:451, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:480;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:451, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:481;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:451, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:482;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:452, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:483;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:452, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:484;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:453, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:485;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:453, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:486;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:309, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:487;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:310, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:487;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:309, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:488;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:309, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:489;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:309, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:490;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:454, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:491;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:454, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:492;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:455, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:493;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:455, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:494;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:456, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:495;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:456, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:496;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:457, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:497;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:457, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:498;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:458, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:499;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:458, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:500;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:459, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:501;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:459, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:502;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:460, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:503;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:460, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:504;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:461, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:505;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:461, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:506;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:462, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:507;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO: 462, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: The nucleotide sequence shown in NO:508;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:463, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:509;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:463, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:510;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:464, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:511;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:464, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:512;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:465, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:513;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:465, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:514;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:466, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:515;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:466, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:516;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:318, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:517;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:319, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:517;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:318, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:518;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:318, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:519;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:318, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:520;
  • the sense strand includes the nucleotide sequence as shown in SEQ ID NO:467, and the antisense strand includes the nucleotide sequence as shown in SEQ ID NO:521;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:467, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:522;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:468, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:523;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:468, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:524;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:469
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:525;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:469, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:526;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:320, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:527;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:321, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:527;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:320, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:528;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:320, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:529;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:320, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:530;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:470, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:531;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:470, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:532;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:322, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:533;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:323, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:533;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:322, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:534;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:322, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:535;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:322, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:536;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:325, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:537;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:326, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:537;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:325, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:538;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:325, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:539;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:325, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:540;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:541;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:330, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:541;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:542;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:543;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:544;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:545;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:333, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:545;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:546;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:332 The nucleotide sequence shown in NO:547;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:548;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:549;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:335, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:549;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:550;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:551;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:552;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:553;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:554;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:555;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:556;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:449, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:636;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:452, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:637;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:452, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:638;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:454, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:639;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:454, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:640;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:457, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:641;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:457, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:642;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:465, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:643;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:465, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:644;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:466, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:645;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:466, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:646;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:467, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:647;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:467, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:648;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:468, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:649;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:468, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:650;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:469, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:651;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:469, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:652;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:470, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:653;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:470, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:654.
  • a double-stranded ribonucleic acid conjugate wherein the double-stranded ribonucleic acid conjugate includes the double-stranded ribonucleic acid as described in any one of [1]-[14], or as described in [15]- [28] The modified double-stranded ribonucleic acid according to any one of the above; and, a conjugation group connected to the double-stranded ribonucleic acid or the modified double-stranded ribonucleic acid.
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate are complementary to form a double-stranded region of the double-stranded ribonucleic acid conjugate, and the 3' end of the sense strand forms a blunt end, and the The 3' end of the antisense strand has 1-2 protruding nucleotides extending out of the double-stranded region;
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate are complementary to form the double-stranded region of the double-stranded ribonucleic acid conjugate, and the 3' end of the sense strand forms a blunt end, and the antisense strand The 3' end forms a blunt end.
  • the double helix structure is double-stranded RNA or a modified double-stranded RNA.
  • the double-stranded ribonucleic acid conjugate is selected from the following:
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:364, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:349;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:365, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:350;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:366, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:359;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:367, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:360;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:368, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:363;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:369, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:351;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:370, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:353;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:371, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:356;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:372, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:343;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:373, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:347;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:374, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:358;
  • the sense strand of the linked conjugate group comprises the nucleotide sequence shown in SEQ ID NO: 375, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 361;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:364, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:517;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:364, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:518;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:365, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:527;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:365, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:528;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:366, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:549;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:366, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:550;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:367, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:553;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO:367, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO:554;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:372, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:487;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:372, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:488;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO:369, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO:533;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:369, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:534;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:370, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:537;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:370, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:538;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:371, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:541;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:371, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:542;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:374, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:545;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:374, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:546;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:557, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:472;
  • the sense strand of the linked conjugate group comprises the nucleotide sequence shown in SEQ ID NO:558, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:475;
  • the sense strand of the linked conjugate group comprises the nucleotide sequence shown in SEQ ID NO:559, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:479;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO: 655, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO: 483;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:655, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:484;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:656, and the reverse The sense strand includes the nucleotide sequence shown in SEQ ID NO:491;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:656, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:492;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO: 657, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO: 497;
  • the sense strand of the linked conjugate group comprises the nucleotide sequence shown in SEQ ID NO: 657, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 498;
  • the sense strand of the linked conjugate group comprises the nucleotide sequence shown in SEQ ID NO: 658, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 513;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO: 658, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO: 514;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:659, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:515;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO: 659, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 516;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:660, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:521;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO: 660, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 522;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO: 661, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 523;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:661, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:524;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO: 662, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO: 525;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:662, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:526;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:663, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:531;
  • the sense strand connecting the conjugate group includes a nucleotide sequence as shown in SEQ ID NO: 663, and the antisense strand includes a nucleotide sequence as shown in SEQ ID NO: 532;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:557, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:473;
  • the sense strand connecting the conjugate group includes the nucleotide sequence shown in SEQ ID NO:558, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:476.
  • a pharmaceutical composition wherein the pharmaceutical composition includes at least one of the following: double-stranded ribonucleic acid as described in any one of [1]-[14], such as any one of [15]-[28]
  • the double-stranded ribonucleic acid modification described in one item is the double-stranded ribonucleic acid conjugate described in any one of [29]-[36].
  • composition according to [37], wherein the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers.
  • a method for inhibiting HMGB1 gene expression in a cell includes combining the cell with the double-stranded ribonucleic acid according to any one of [1]-[14], according to [15] -The double-stranded ribonucleic acid modification according to any one of [28], the double-stranded ribonucleic acid conjugate according to any one of [29]-[36], or the double-stranded ribonucleic acid conjugate according to any one of [37]-[38] contact with the pharmaceutical composition described in the item.
  • HMGB1 gene Abnormal expression of HMGB1 gene in the body, more specifically abnormal high expression of HMGB1 gene
  • the double-stranded ribonucleic acid provided by the present disclosure can combine in cells to form an RNA-induced silencing complex (RISC), cleave the mRNA transcribed by the HMGB1 gene, efficiently and specifically inhibit the expression of the HMGB1 gene, and is used for treatment Including non-alcoholic steatohepatitis, sepsis, arthritis, colitis, acute lung injury, colorectal cancer, gastric cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma HMGB1-related diseases including tumors, multiple myeloma, and atherosclerosis.
  • RISC RNA-induced silencing complex
  • the double-stranded ribonucleic acid is siRNA.
  • siRNA targets and degrades the transcript product of HMGB1 gene, mRNA, exerts the effect of RNA interference and inhibits the protein expression of HMGB1 gene. It is a method with high inhibition rate and good specificity. HMGB1 inhibitors.
  • the present disclosure modifies double-stranded ribonucleic acid to obtain a double-stranded ribonucleic acid modified product.
  • the double-stranded ribonucleic acid modified product has high stability and is suitable for use in in vivo disease treatment.
  • the double-stranded RNA modification is a siRNA modification, which has high stability and good inhibitory activity.
  • the present disclosure connects a conjugation group to double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications to obtain a conjugate of double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications, which can be used to deliver tissues and cells.
  • Medium and high-efficiency targeted delivery reduces the impact of double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications on non-targeted normal tissues and cells, and improves its safety in clinical disease treatment.
  • the double-stranded ribonucleic acid conjugate is an siRNA conjugate. While maintaining the inhibitory activity and stability of siRNA, it also has organ or tissue targeting, which can reduce the impact on other tissues or organs and reduce the use of siRNA molecules. quantity, can achieve the purpose of reducing toxicity and reducing costs.
  • the conjugation group in the present disclosure is a group (GalNAc) with the structure shown in Formula I.
  • GalNAc can be used for targeted delivery to liver cells and tissues, and can be used to effectively inhibit the expression of the HMGB1 gene in the liver.
  • HMGB1 HMGB1
  • HMG-1 HMG1
  • HMG3 SBP-1
  • GenBank GenBank
  • OMIM Online Mendelian Inheritance in Man
  • HMGB1 gene can be a wild-type HMGB1 gene or a HMGB1 gene mutant with sequence variation. Many sequence variations in the HMGB1 gene have been identified and can be found, for example, in NCBIdbSNP and UniProt (see, eg, ncbi.nlm.nih.gov/snp).
  • polypeptide refers to a string of at least two amino acid residues linked to each other by covalent bonds (e.g., peptide bonds), which may be recombinant polypeptides, natural polypeptides, or synthetic polypeptides.
  • a polypeptide may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids.
  • the term also includes amino acid polymers that have been modified (e.g., disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component).
  • target sequence refers to the contiguous portion of the nucleotide sequence of the mRNA molecule formed during the transcription of the target gene, including the mRNA as a product of RNA processing of the primary transcript.
  • the target sequence is no less than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120,
  • the target gene is the HMGB1 gene.
  • the target portion of the sequence will be at least long enough to serve as a substrate for iRNA-directed cleavage at or near the nucleotide sequence portion of the mRNA molecule formed during transcription of the HMGB1 gene.
  • G", “C”, “A”, “T” and “U” generally represent the bases of guanine, cytosine, adenine, thymine and uracil, respectively, but it is also generally known in the art that “G”, “C”, “A”, “T” and “U” each generally represent nucleotides containing guanine, cytosine, adenine, thymine and uracil as bases, respectively, which is a common way to represent deoxyribonucleic acid sequences and/or ribonucleic acid sequences, so in the context of the present disclosure, the meanings represented by “G”, “C”, “A”, “T”, “U” include the above-mentioned various possible situations.
  • ribonucleotide or “nucleotide” can also refer to a modified nucleotide (as further described below) or an alternative replacement part.
  • guanine, cytosine, adenine and uracil can be replaced by other parts without substantially changing the base pairing properties of an oligonucleotide (including a nucleotide having such a replacement part).
  • a nucleotide comprising inosine as its base can be base paired with a nucleotide comprising adenine, cytosine or uracil.
  • a nucleotide containing uracil, guanine or adenine can be replaced by a nucleotide containing, for example, inosine in the nucleotide sequence of the dsRNA characterized by the present invention.
  • adenine and cytosine anywhere in the oligonucleotide can be replaced by guanine and uracil, respectively, to form a G-U wobble base pairing with the target mRNA. Sequences containing such replacement parts are suitable for the compositions and methods characterized by the present invention.
  • RNAi agent RNAi agent
  • RNA interference agent RNA interference agent
  • siRNA siRNA and mediate silencing induced by RNA.
  • RISC RISC complex
  • iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi).
  • RNAi RNA interference
  • An iRNA modulates, eg, inhibits, the expression of a target gene in a cell, such as a cell of a subject (eg, a mammalian subject).
  • double-stranded ribonucleic acid double-stranded RNA (dsRNA) molecule
  • dsRNA double-stranded RNA
  • dsRNA double-stranded RNA
  • double-stranded ribonucleic acid triggers the degradation of target RNA, such as mRNA, through a post-transcriptional gene silencing mechanism (referred to herein as RNA interference or RNAi).
  • target RNA such as mRNA
  • RNA interference post-transcriptional gene silencing mechanism
  • each strand of a dsRNA molecule typically, the majority of the nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as detailed herein, each or both strands may also include one or more non-ribonucleotides Acids, for example, deoxyribonucleotides and/or modified nucleotides. Additionally, as used in this disclosure, "double-stranded ribonucleic acid" may include ribonucleotides with chemical modifications, phosphate backbones, and the like. These modifications may include all types of modifications disclosed herein or known in the art.
  • isonucleotide refers to compounds in which the position of the base in the ribose ring is changed in the nucleotide, for example, the base is not attached to the 1'-position of the ribose ring, but is With the 2'-position or 3'-position of the ribose ring Compounds formed by joining together.
  • the double-stranded ribonucleic acid of the present disclosure is an siRNA that interacts with the mRNA sequence transcribed by the target gene (eg, the mRNA sequence transcribed by the C gene) to direct cleavage of the target RNA.
  • the target gene eg, the mRNA sequence transcribed by the C gene
  • Dicer ribonuclease III-like enzyme
  • processes dsRNA into 19-23 base pair short interfering RNA with a characteristic two-base 3' overhang (Bernstein et al.
  • siRNAs are subsequently incorporated into the RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA duplex, making it possible for the complementary antisense strand to guide target recognition (Nykanen et al., (2001) Cell 107:309).
  • RISC RNA-induced silencing complex
  • one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir et al., (2001) Genes Dev. 15: 188).
  • overhanging nucleotide refers to a protruding or Multiple unpaired nucleotides, or vice versa.
  • “Blunt end” or “blunt end” means that there are no unpaired nucleotides, ie, no nucleotide overhangs, at that end of the double-stranded ribonucleic acid.
  • a "blunt-ended" double-stranded RNA is a dsRNA that is double-stranded throughout its length, ie, it has no nucleotide overhangs at either end of the molecule.
  • antisense strand refers to the strand of a region of double-stranded ribonucleic acid that is substantially complementary to a target sequence (eg, derived from human HMGB1 mRNA).
  • a target sequence eg, derived from human HMGB1 mRNA.
  • mismatches are most tolerated in the terminal region, and if mismatches occur, they are usually in one or more regions at the terminal end, such as the 5' and/or Within 5, 4, 3, 2 or 1 nucleotide of the 3' end.
  • sense strand refers to a double-stranded nucleic acid strand containing a region that is substantially complementary to a region of the antisense strand.
  • the terms “complementary” or “reverse complementary” are used interchangeably and have the meaning well known to those skilled in the art, that is, in a double-stranded nucleic acid molecule, the bases on one strand are connected to the bases on the other strand. Paired in complementary ways.
  • the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or uracil (U) in RNA);
  • the purine base guanine (C) always pairs with the pyrimidine base Pairs with cytosine (G).
  • Each base pair consists of a purine and a pyrimidine.
  • mismatch in this field means that in double-stranded nucleic acids, the bases at corresponding positions do not pair in a complementary manner.
  • substantially reverse complementary means that there are no more than 3 base mismatches between the two nucleotide sequences involved, that is, there are 1, 2, and 2 base mismatches between the two nucleotide sequences involved. or 3 base mismatches; “complete complementarity” means that there are no base mismatches between the two nucleotide sequences.
  • suppression may be used interchangeably with “reduction,” “silencing,” “downregulation,” “suppression” and other similar terms and includes any level of suppression.
  • HMGB1 gene includes inhibiting any HMGB1 gene (such as, for example, a mouse HMGB1 gene, a rat HMGB1 gene, a monkey HMGB1 gene, or a human HMGB1 gene) as well as variants (eg, naturally occurring variants) of the HMGB1 gene, or Expression of mutants.
  • the HMGB1 gene may be a wild-type HMGB1 gene, a mutant HMGB1 gene, or in the case of a genetically manipulated cell, cell population or organism, a transgenic HMGB1 gene.
  • “Inhibition of HMGB1 gene expression” includes any level of inhibition of the HMGB1 gene, such as at least partial inhibition of the expression of the HMGB1 gene, such as inhibition of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%.
  • each independently means that at least two groups (or ring systems) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances.
  • substituent X and substituent Y are each independently hydrogen, hydroxyl, alkyl or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen, hydroxyl, alkyl or aryl. ;Similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen, hydroxyl, alkyl or aryl.
  • alkyl includes straight-chain, branched or cyclic saturated alkyl groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclohexyl, and the like. group.
  • C1-6 in “C1-6 alkyl” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear, branched or cyclic form. .
  • alkoxy refers to an alkyl group attached to the remainder of the molecule through an oxygen atom (-O-alkyl), wherein said alkyl group is as defined herein.
  • alkoxy include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n- Pentyloxy etc.
  • treatment refers to exposing a subject to (e.g., administering) a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition after suffering from a disease, so that the subject is not exposed to the disease. Reducing the symptoms of the disease does not necessarily mean that they must be completely suppressed. Suffering from a disease means that the body has symptoms of the disease.
  • prevention refers to: by exposing a subject to (e.g., administering) the double-stranded ribonucleic acid, double-stranded ribonucleic acid modification, double-stranded ribonucleic acid conjugate, pharmaceutical composition of the present disclosure before suffering from the disease, Thus, reducing the symptoms of a disease compared with no exposure does not necessarily mean that the disease must be completely suppressed.
  • an effective amount refers to an amount or dosage of the double-stranded ribonucleic acid, double-stranded ribonucleic acid modification, double-stranded ribonucleic acid conjugate or pharmaceutical composition of the present invention, which after administration to a patient in single or multiple doses, Produce the desired effect in patients in need of treatment or prophylaxis.
  • the effective amount can be readily determined by the attending physician, who is one of skill in the art, by considering various factors such as: the species of the mammal; its size, age and general health; the specific disease involved; the extent or severity of the disease; The individual patient's response; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; and the use of any concomitant therapy.
  • HMGB1 gene is a disease or disorder associated with inflammatory response and tumor cell migration.
  • disease associated with abnormal expression of the HMGB1 gene includes diseases, disorders or conditions that would benefit from reduced expression of HMGB1 (ie, "HMGB1-related disease”). Such diseases are typically closely related to signaling pathways involving inflammatory factors.
  • Non-limiting examples of diseases associated with abnormal expression of the HMGB1 gene include: non-alcoholic steatohepatitis, sepsis, arthritis, colitis, acute lung injury, colorectal cancer, gastric cancer, myelodysplastic syndrome, acute myeloid Leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma, atherosclerosis, etc. (Harriet Gaskell et al., High-Mobility Group Box-1 and Liver Disease, Hepatol Commun.
  • HMGB1 enhances chemotherapy resistance in multiple myeloma cells by activating the nuclear factor- ⁇ B pathway,Exp Ther Med.2021Jul;22(1):705.
  • Angel Y F Kam et al. Targeting High Mobility Group Box-1(HMGB1)Promotes Cell Death in Myelodysplastic Syndrome,Clin Cancer Res.2019Jul 1;25(13):4155-4167.doi:10.1158/1078-0432.CCR-18-3517.Epub 2019Apr 5.
  • pharmaceutically acceptable excipients or “pharmaceutically acceptable carriers” refers to auxiliary materials widely used in the field of pharmaceutical production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be used in the desired manner. rate dissolution, or promote effective absorption of the active ingredient in the subject to whom it is administered.
  • Pharmaceutically acceptable excipients may be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients in the composition).
  • Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, and anti-adhesive agents. , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.
  • compositions of the present disclosure may be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding and/or lyophilizing processes.
  • the methods of administration can be varied or adapted in any applicable manner to meet the needs of the nature of the drug, convenience of the patient and medical staff, and other relevant factors.
  • mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • domestic animals e.g., cows, sheep, cats, dogs and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats.
  • a first aspect of the present disclosure provides a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of HMGB1 gene.
  • dsRNA double-stranded ribonucleic acid
  • One strand of the double-stranded ribonucleic acid is the antisense strand.
  • the antisense strand is complementary to the mRNA sequence formed during the expression of the target gene (i.e., the HMGB1 gene) and is used to guide the transcription product of the target mRNA (i.e., the HMGB1 gene). ) cutting.
  • the other sense strand in the double-stranded RNA includes a double-stranded region that is partially complementary and fully complementary to the antisense strand to form a double-stranded RNA.
  • double-stranded ribonucleic acid serves as a substrate for endonuclease (Dicer) and is cleaved into small fragments of dsRNA, that is, siRNA.
  • the double-stranded ribonucleic acid is siRNA.
  • siRNA assembles to form the RNA-induced silencing complex (RISC) RISC complex, which cleaves the target mRNA and inhibits the expression of the HMGB1 gene.
  • RISC RNA-induced silencing complex
  • siRNA that binds to the target mRNA is designed.
  • the target sequence is selected from the nucleotide sequences shown in any one of SEQ ID NOs: 1 to 16 and SEQ ID NOs: 560-567.
  • the target sequence is selected from the nucleotide sequences shown in any one of SEQ ID NO: 17-68, SEQ ID NO: 560, and SEQ ID NO: 562-569.
  • the nucleotide sequence shown in SEQ ID NO:1 includes the nucleotide sequence shown in SEQ ID NO:17 ⁇ 19.
  • the nucleotide sequence shown in SEQ ID NO:2 includes the nucleotide sequence shown in SEQ ID NO:20-24.
  • the nucleotide sequence shown in SEQ ID NO:3 includes the nucleotide sequence shown in SEQ ID NO:25 ⁇ 27.
  • the nucleotide sequence shown in SEQ ID NO:4 includes the nucleotide sequence shown in SEQ ID NO:28-30.
  • the nucleotide sequence shown in SEQ ID NO:5 includes the nucleotide sequence shown in SEQ ID NO:31 ⁇ 36.
  • the nucleotide sequence shown in SEQ ID NO: 6 includes the nucleotide sequence shown in SEQ ID NO: 37-40.
  • the nucleotide sequence shown in SEQ ID NO:7 includes the nucleotide sequence shown in SEQ ID NO:41 ⁇ 42.
  • the nucleotide sequence shown in SEQ ID NO:8 includes the nucleotide sequence shown in SEQ ID NO:43 ⁇ 45.
  • the nucleotide sequence shown in SEQ ID NO:9 includes the nucleotide sequence shown in SEQ ID NO:46-47.
  • the nucleotide sequence shown in SEQ ID NO: 10 includes the nucleotide sequence shown in SEQ ID NO: 48-49.
  • the nucleotide sequence shown in SEQ ID NO: 11 includes the nucleotide sequence shown in SEQ ID NO: 50-51.
  • the nucleotide sequence shown in SEQ ID NO: 12 includes the nucleotide sequence shown in SEQ ID NO: 52-54.
  • the nucleotide sequence shown in SEQ ID NO: 13 includes the nucleotide sequence shown in SEQ ID NO: 55-58.
  • the nucleotide sequence shown in SEQ ID NO:14 includes the nucleotide sequence shown in SEQ ID NO:59 ⁇ 61.
  • the nucleotide sequence shown in SEQ ID NO: 15 includes the nucleotide sequence shown in SEQ ID NO: 62-66.
  • the nucleotide sequence shown in SEQ ID NO:16 contains the nucleotide sequence shown in SEQ ID NO:67-68.
  • the nucleotide sequence shown in SEQ ID NO:561 includes the nucleotide sequence shown in SEQ ID NO:568 ⁇ 569.
  • the antisense strand comprises sequence B that differs by no more than 3 nucleotides from the reverse complement of at least 15 contiguous nucleotides in the target sequence.
  • the starting nucleotide is selected in the target sequence in the direction from the 5' end to the 3' end, and at least 15 nucleotides extending in the 3' direction including the starting nucleotide are used as the siRNA.
  • the antisense strand contains the reverse complement of the nucleotide sequence corresponding to the binding region.
  • the starting nucleotide can be a nucleotide at any position of the target sequence, as long as at least 15 consecutive nucleotides (including the starting nucleotide) can be obtained based on the starting nucleotide extending in the 3' direction of the target sequence. nucleotide at the starting position).
  • the nucleotide sequence of the antisense strand may be completely complementary or substantially complementary to the target sequence.
  • the nucleotide sequence of the antisense strand contains no more than 3 mismatched bases with the target sequence. For example, there are 1, 2, or 3 mismatched bases.
  • the nucleotide sequence of the antisense strand is completely complementary to the target sequence, there are no mismatched bases between the nucleotide sequence of the antisense strand and the target sequence.
  • the antisense strand consists of at least 15 nucleotides. In some embodiments, the antisense strand consists of 15-28 composed of nucleotides. For example, the antisense strand is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length.
  • the antisense strand consists of 19-25 nucleotides, more preferably 19-23 nucleotides, and most preferably 19, 21 or 23 nucleotides.
  • the antisense strand contains sequence B that is identical to the reverse complement of a sequence consisting of at least 15 consecutive nucleotides on the target sequence.
  • the antisense strand contains sequence B that is identical to the reverse complement of a sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • sequence B is identical to the reverse complement of a sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • the sequence B comprised in the antisense strand differs by 1 nucleotide from the reverse complementary sequence of a sequence consisting of at least 15 consecutive nucleotides on the target sequence.
  • the antisense strand contains sequence B that differs by 1 nucleotide from the reverse complement of a sequence consisting of 15-28 nucleotides on the target sequence.
  • sequence B that differs by 1 nucleotide from the reverse complement of a sequence consisting of 15-28 nucleotides on the target sequence.
  • the differential nucleotides are located at the 3' end of sequence B.
  • the sense strand comprises sequence A that differs by no more than 3 nucleotides from at least 15 consecutive nucleotides in the target sequence.
  • the sense strand includes a region complementary to the antisense strand, and the nucleotide sequence of the sense strand is identical or substantially identical to the sequence of the binding region of the antisense strand on the target sequence. Therefore, the nucleotide sequence of the sense strand is at least 15 consecutive nucleotides in the target sequence that binds the antisense strand; alternatively, the nucleotide sequence of the sense strand is the same as at least 15 consecutive nucleotides in the target sequence that binds the antisense strand.
  • the sense strand consists of at least 15 nucleotides. In some embodiments, the sense strand consists of 15-28 nucleotides. For example, the sense strand is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length.
  • the sense strand consists of 19-25 nucleotides, more preferably 19-23 nucleotides, and most preferably 19, 21 or 23 nucleotides.
  • the sense strand includes sequence A that is identical to the sequence consisting of at least 15 consecutive nucleotides on the target sequence.
  • the sense strand contains sequence A that is identical to the sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • sequence A that is identical to the sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • there are 19-25 contiguous nucleotides on the target sequence more preferably 19-23 contiguous nucleotides on the target sequence, and most preferably 19, 21 or 23 contiguous nucleotides on the target sequence.
  • the sense strand contains sequence A that differs by 1 nucleotide from a sequence consisting of at least 15 consecutive nucleotides on the target sequence.
  • the sense strand contains sequence A that differs by 1 nucleotide from the sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • sequence A that differs by 1 nucleotide from the sequence consisting of 15-28 consecutive nucleotides on the target sequence.
  • there are 19-25 contiguous nucleotides on the target sequence more preferably 19-23 contiguous nucleotides on the target sequence, and most preferably 19, 21 or 23 contiguous nucleotides on the target sequence.
  • the different nucleotides are located at the 3' end of sequence A.
  • the length of the sense strand and the length of the antisense strand may be the same or different.
  • the sense strand and the antisense strand have the same length.
  • the length ratio of the sense strand/antisense strand is 15/15, 16/16, 17/17, 18/18, 19/19, 20 /20, 21/21, 22/22, 23/23, 24/24, 25/25, 26/26, 27/27 or 28/28.
  • the length ratio of sense strand/antisense strand is 19/19, 20/20, 21/21, 22/22, 23/23, 24/24 or 25/25, more preferably 19/19, 20/20 , 21/21, 22/22 or 23/23, most preferably 19/19, 21/21 or 23/23; in some preferred embodiments, the length ratio of the sense strand/antisense strand is 19/21 or 21 /twenty three.
  • the sense and antisense strands are different lengths.
  • the length ratio of sense strand/antisense strand is 19/20, 19/21, 19/22, 19/23, 19/24, 19/25, 19/26, 20/19, 20/21, 20/ 22, 20/23, 20/24, 20/25, 20/26, 21/19, 21/20, 21/22, 21/23, 21/24, 21/25, 21/26, 22/19, 22/20, 22/21, 22/ 23, 22/24, 22/25, 22/26, 23/19, 23/20, 23/21, 23/22, 23/24, 23/25 or 23/26, etc.
  • the sense strand and the antisense strand may be completely complementary or substantially complementary. When the two are substantially complementary, there will be no more than 3 mismatched bases in the double-stranded region formed by the sense strand and the antisense strand.
  • the sense strand, the antisense strand, or a combination thereof has overhanging nucleotides extending out of the double-stranded region.
  • the number of overhanging nucleotides may be 1 or more, for example, 1 or 2.
  • the protruding 1-2 nucleotides can be located at the 5' end, 3' end or both ends of any antisense strand or sense strand, and each protruding nucleotide can be any type of nucleotide.
  • the sense strand is complementary to the antisense strand to form the double-stranded region, and the 3' end of the sense strand has 1-2 protruding nucleosides extending out of the double-stranded region. acid, the 3' end of the antisense strand forms a blunt end.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the antisense strand has 1-2 protruding cores extending out of the double-stranded region. The 3' end of the sense strand forms a blunt end.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand each have 1-2 strands extending out of the double-stranded region. Overhanging nucleotides in the chain region.
  • the sense strand and the antisense strand are complementary to each other to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the antisense strand and the target sequence may be completely complementary or substantially complementary; the sense strand and the antisense strand may be completely complementary or substantially complementary. Therefore, the following target sequences SEQ ID NO:17 ⁇ SEQ ID NO:68, SEQ ID NO:560, SEQ ID NO:562 ⁇ SEQ ID NO:567, SEQ ID NO:568 ⁇ SEQ ID NO:569 and those that can be compared with
  • the description of siRNAs that are complementary to these target sequences, for each siRNA's antisense strand includes the target sequence that is complementary to it (for example, SEQ ID NO: 17 ⁇ SEQ ID NO: 68, SEQ ID NO: 560, SEQ ID NO: 562 ⁇ SEQ ID NO:567, SEQ ID NO:568 ⁇ SEQ ID NO:569) are basically complementary, that is, the nucleotide sequence of the antisense strand of each siRNA can exist with There are base mismatches in the
  • the base mismatch or base difference may be a mismatch or difference that differs from the target sequence by no more than 3 bases, for example, the mismatch base or the difference base is 1, 2 or 3. It should be noted that for any of the target sequences SEQ ID NO:1 ⁇ SEQ ID NO:7 and SEQ ID NO:561, the above-mentioned methods for the target sequences SEQ ID NO:17 ⁇ SEQ ID NO:68 and SEQ ID NO:68 are also applicable.
  • each The nucleotide sequence of the antisense strand of siRNA may have base mismatches with the corresponding target sequence, and the nucleotide sequence of the sense strand of each siRNA may have base differences with the corresponding target sequence.
  • the base mismatch or base difference may be a mismatch or difference that differs from the target sequence by no more than 3 bases, for example, the mismatch base or the difference base is 1, 2 or 3.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:17
  • the nucleotide sequence of the antisense strand is SEQ ID NO:17
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA1 shown in Table 1.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 18, and the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 18.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:18
  • the nucleotide sequence of the antisense strand is SEQ ID NO:18
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:18
  • the nucleotide sequence of the antisense strand is SEQ ID NO:18
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any one of siRNA2 to siRNA9 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:19
  • the nucleotide sequence of the antisense strand is SEQ ID NO:19
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:19
  • the nucleotide sequence of the antisense strand is SEQ ID NO:19
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:19
  • the nucleotide sequence of the antisense strand is SEQ ID NO:19
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA10 to siRNA15 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:20
  • the nucleotide sequence of the antisense strand is SEQ ID NO:20
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA111 shown in Table 1-1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:21
  • the nucleotide sequence of the antisense strand is SEQ ID NO:21
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA16 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:22
  • the nucleotide sequence of the antisense strand is SEQ ID NO:22
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA17 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:23
  • the nucleotide sequence of the antisense strand is SEQ ID NO:23
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA18 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:24
  • the nucleotide sequence of the antisense strand is SEQ ID NO:24 19 consecutive nucleotides in the sequence shown
  • the acid sequence consists of the reverse complement of sequence B. Furthermore, the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:24
  • the nucleotide sequence of the antisense strand is SEQ ID NO:24
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO: 24, and the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO: 24.
  • the 3' ends of the sense strand and the antisense strand each have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded RNA is any one of siRNA19 to siRNA24 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:25
  • the nucleotide sequence of the antisense strand is SEQ ID NO:25
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO: 25, and the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO: 25.
  • the 3' ends of the sense strand and the antisense strand each have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:25
  • the nucleotide sequence of the antisense strand is SEQ ID NO:25
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA25 to siRNA28, siRNA112 to siRNA114, siRNA167, siRNA199, and siRNA201 shown in Table 1 or Table 1-1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:26
  • the nucleotide sequence of the antisense strand is SEQ ID NO:26
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:26
  • the nucleotide sequence of the antisense strand is SEQ ID NO:26
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:26
  • the nucleotide sequence of the antisense strand is SEQ ID NO:26
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA29 to siRNA34 and siRNA115 to siRNA116 shown in Table 1 or Table 1-1.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 27, and the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 27.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA35 shown in Table 1.
  • the nucleotide sequence of the sense strand is the 19 consecutive nucleotides in the sequence shown in SEQ ID NO:28.
  • the nucleotide sequence of the antisense strand is sequence A, which is composed of continuation nucleotides.
  • the nucleotide sequence of the antisense strand is sequence B, which is the reverse complement of the sequence B composed of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:28.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:28
  • the nucleotide sequence of the antisense strand is SEQ ID NO:28
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO: 28, and the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO: 28.
  • the 3' ends of the sense strand and the antisense strand each have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA36 to siRNA41 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:29
  • the nucleotide sequence of the antisense strand is SEQ ID NO:29
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:29
  • the nucleotide sequence of the antisense strand is SEQ ID NO:29
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:29
  • the nucleotide sequence of the antisense strand is SEQ ID NO:29
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any one of siRNA42 to siRNA56 and siRNA117 shown in Table 1 or Table 1-1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA57 to siRNA70 and siRNA118 to siRNA119 shown in Table 1 or Table 1-1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:31
  • the nucleotide sequence of the antisense strand is SEQ ID NO:31
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA71 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:32
  • the nucleotide sequence of the antisense strand is SEQ ID NO:32
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA72 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:33
  • the nucleotide sequence of the antisense strand is SEQ ID NO:33
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA73 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:34
  • the nucleotide sequence of the antisense strand is SEQ ID NO:34
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA74 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:35
  • the nucleotide sequence of the antisense strand is SEQ ID NO:35
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA75 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:36
  • the nucleotide sequence of the antisense strand is SEQ ID NO:36
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA76 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:37
  • the nucleotide sequence of the antisense strand is SEQ ID NO:37
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA77 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:38
  • the nucleotide sequence of the antisense strand is SEQ ID NO:38
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded RNA is siRNA78 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:39
  • the nucleotide sequence of the antisense strand is SEQ ID NO:39
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA79 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:40
  • the nucleotide sequence of the antisense strand is SEQ ID NO:40
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA80 shown in Table 1.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 41
  • the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 41.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA120 shown in Table 1-1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:42
  • the nucleotide sequence of the antisense strand is SEQ ID NO:42
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA81 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:43
  • the nucleotide sequence of the antisense strand is SEQ ID NO:43
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA82 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:44
  • the nucleotide sequence of the antisense strand is SEQ ID NO:44
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA83 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:45
  • the nucleotide sequence of the antisense strand is SEQ ID NO:45
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA84 to siRNA86 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:46
  • the nucleotide sequence of the antisense strand is SEQ ID NO:46
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA87 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:47
  • the nucleotide sequence of the antisense strand is SEQ ID NO:47
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA88 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:48
  • the nucleotide sequence of the antisense strand is SEQ ID NO:48
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA89 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:49
  • the nucleotide sequence of the antisense strand is SEQ ID NO:49
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA90 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:50
  • the nucleotide sequence of the antisense strand is SEQ ID NO:50
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA91 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:51
  • the nucleotide sequence of the antisense strand is SEQ ID NO:51
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA92 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:52
  • the nucleotide sequence of the antisense strand is SEQ ID NO:52
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA93 shown in Table 1.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 53
  • the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 53.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA94 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:54
  • the nucleotide sequence of the antisense strand is SEQ ID NO:54
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded RNA is siRNA95 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:55
  • the nucleotide sequence of the antisense strand is SEQ ID NO:55
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA96 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:56
  • the nucleotide sequence of the antisense strand is SEQ ID NO:56
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA97 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:57
  • the nucleotide sequence of the antisense strand is SEQ ID NO:57
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA98 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:58
  • the nucleotide sequence of the antisense strand is SEQ ID NO:58
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA99 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:59
  • the nucleotide sequence of the antisense strand is SEQ ID NO:59
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA100 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:60
  • the nucleotide sequence of the antisense strand is SEQ ID NO:60
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded RNA is siRNA101 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:61
  • the nucleotide sequence of the antisense strand is SEQ ID NO:61
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded RNA is siRNA102 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:62
  • the nucleotide sequence of the antisense strand is SEQ ID NO:62
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA103 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:63
  • the nucleotide sequence of the antisense strand is SEQ ID NO:63
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA104 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:64
  • the nucleotide sequence of the antisense strand is SEQ ID NO:64
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA105 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:65
  • the nucleotide sequence of the antisense strand is SEQ ID NO:65
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA106 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:66
  • the nucleotide sequence of the antisense strand is SEQ ID NO:66
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA107 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:67
  • the nucleotide sequence of the antisense strand is SEQ ID NO:67
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA108 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:68
  • the nucleotide sequence of the antisense strand is SEQ ID NO:68
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA109 to siRNA110 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:560
  • the nucleotide sequence of the antisense strand is SEQ ID NO:560
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:560
  • the nucleotide sequence of the antisense strand is SEQ ID NO:560
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:560
  • the nucleotide sequence of the antisense strand is SEQ ID NO:560
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA171 to siRNA179 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:568, and the nucleotide sequence of the antisense strand is SEQ ID NO:568
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:568, and the nucleotide sequence of the antisense strand is SEQ ID NO:568
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:568, and the nucleotide sequence of the antisense strand is SEQ ID NO:568
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA180 to siRNA182 and siRNA318 to siRNA325 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:569
  • the nucleotide sequence of the antisense strand is SEQ ID NO:569
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA183 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:562, and the nucleotide sequence of the antisense strand is SEQ ID NO:562
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA184 to siRNA188 shown in Table 1.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 563
  • the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO: 563.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is a sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO: 563
  • the nucleotide sequence of the antisense strand is a sequence B that is the reverse complement of the sequence consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO: 563.
  • the 3' ends of the sense strand and the antisense strand each have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:563, and the nucleotide sequence of the antisense strand is SEQ ID NO:563
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA189 and siRNA326 to siRNA334 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:564, and the nucleotide sequence of the antisense strand is SEQ ID NO:564
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:564, and the nucleotide sequence of the antisense strand is SEQ ID NO:564
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA190 to siRNA197 and siRNA335 to siRNA338 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:565, and the nucleotide sequence of the antisense strand is SEQ ID NO:565
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:565, and the nucleotide sequence of the antisense strand is SEQ ID NO:565
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any one of siRNA198, siRNA339 to siRNA343 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:566, and the nucleotide sequence of the antisense strand is SEQ ID NO:566
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:566, and the nucleotide sequence of the antisense strand is SEQ ID NO:566
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded RNA is any one of siRNA168 to siRNA169, siRNA200, siRNA202, and siRNA344 to siRNA350 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:567
  • the nucleotide sequence of the antisense strand is SEQ ID NO:567
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA170 shown in Table 1.
  • the sense strand includes the nucleotide sequence shown in any one of SEQ ID NOs: 69-178, SEQ ID NOs: 376-411, and SEQ ID NOs: 570-602, wherein The antisense strand includes the nucleotide sequence shown in any one of SEQ ID NOs: 179-288, SEQ ID NOs: 412-447, and SEQ ID NOs: 603-635.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NOs: 289-298, and the antisense strand includes the nucleotide sequence shown in any one of SEQ ID NOs: 299-308. nucleotide sequence.
  • the double-stranded ribonucleic acid is selected from any siRNA as shown in Table 1 or Table 1-1.
  • the siRNA provided by the present disclosure has high binding specificity to target mRNA (HMGB1 mRNA), has good silencing activity of target mRNA, can significantly inhibit HMGB1 gene expression, and is used to treat non-alcoholic steatohepatitis and sepsis. , arthritis, colitis, acute lung injury, colorectal cancer, gastric cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma, and atherosclerosis HMGB1-related diseases, etc.
  • the present disclosure provides an siRNA composition comprising any one or a combination of two or more of the siRNAs shown in Table 1 or Table 1-1.
  • each nucleotide of the sense strand is independently a modified nucleotide or an unmodified nucleotide. In some embodiments, each nucleotide of the antisense strand is independently a modified nucleotide or an unmodified nucleotide.
  • any two adjacent nucleotides in the sense strand are connected by a phosphodiester bond or a phosphorothioate diester bond. In some embodiments, any two adjacent nucleotides in the antisense strand are connected by a phosphodiester bond or a phosphorothioate diester bond.
  • the 5' terminal nucleotide of the sense strand is linked to a 5' phosphate group or a 5' phosphate derivative group. In some embodiments, the 5' terminal nucleotide of the antisense strand is linked to a 5' phosphate group or a 5' phosphate derivative group.
  • the structure of the 5' phosphate group is:
  • the structures of the 5' phosphate derivative group include but are not limited to: wait.
  • Base represents a base, such as A, U, G, C or T.
  • R' is hydroxyl or substituted by various groups known to those skilled in the art, for example, 2'-fluoro (2'-F) modified nucleotides, 2'-alkoxy modified nucleotides , 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-substituted alkyl modified nucleotides, 2'-deoxyribonucleotides.
  • 2'-fluoro (2'-F) modified nucleotides 2'-alkoxy modified nucleotides
  • 2'-substituted alkoxy modified nucleotides 2'-alkyl modified nucleotides
  • 2'-substituted alkyl modified nucleotides 2'-deoxyribonucleotides.
  • a second aspect of the present disclosure provides a double-stranded ribonucleic acid modification.
  • the double-stranded ribonucleic acid modification is an siRNA modification.
  • siRNA modifications can improve the stability of siRNA while maintaining high HMGB1 mRNA inhibitory activity.
  • double-stranded ribonucleic acid modifications comprise modification of at least one nucleotide.
  • Nucleotide modification The decoration is selected from at least one selected from the group consisting of modification of the ribose group and modification of the base.
  • “modification of nucleotides” refers to nucleotides or nucleotide derivatives formed by replacing the 2' hydroxyl group of the ribose group of the nucleotide with other groups, or a base on the nucleotide. A nucleotide whose base is a modified base. The modification of the nucleotide will not cause the siRNA's function of inhibiting gene expression to be significantly weakened or lost.
  • modified nucleotides disclosed in JK Watts, GF Deleavey, and MJ Damha, Chemically modified siRNA: tools and applications. Drug Discov Today, 2008, 13(19-20):842-55, can be selected.
  • the stability of siRNA can be improved through nucleotide modification and its high inhibition efficiency of the HMGB1 gene can be maintained.
  • the modified nucleotide has the following structure:
  • Base represents a base, such as A, U, G, C or T.
  • the hydroxyl group at the 2' position of the ribose group is substituted by R.
  • the hydroxyl group at the 2' position of these ribose groups can be substituted by various groups known to those skilled in the art, for example, 2'-fluoro (2'-F) modified nucleotides, 2'-alkoxy modified nucleotides, 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-substituted alkyl modified nucleotides, 2'-deoxyribonucleotides.
  • the 2'-alkoxy modified nucleotide is a 2'-methoxy (2'-OMe, 2'-O- CH3 ) modified nucleotide, and the like.
  • the modification of the nucleotide is a modification of a base.
  • the modification of the base may be various types of modifications known to those skilled in the art. Exemplary base modifications include but are not limited to m 6 A, ⁇ , m 1 A, m 5 A, ms 2 i 6 A, i 6 A, m 3 C, m 5 C, ac 4 C, m 7 G, m 2,2 G, m 2 G, m 1 G, Q, m 5 U, mcm 5 U, ncm 5 U, ncm 5 Um, D, mcm 5 s 2 U, Inosine(I), hm 5 C , s 4 U, s 2 U, azobenzene, Cm, Um, Gm, t 6 A, yW, ms 2 t 6 A or its derivatives.
  • a nucleotide derivative refers to a nucleotide that can replace a nucleotide in a nucleic acid, but is structurally different from adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribose Nucleotides or thymine deoxyribonucleotide compounds.
  • the nucleotide derivative may be an isonucleotide, a bridged nucleic acid (BNA), or acyclic nucleotide.
  • BNA refers to constrained or inaccessible nucleotides.
  • BNA may contain a five-membered ring, a six-membered ring, or a seven-membered ring bridged structure with a "fixed" C3'-endoglycocondensation.
  • the bridge is usually incorporated into the 2'-, 4'-position of the ribose to provide a 2', 4'-BNA nucleotide, such as LNA, ENA, cET, etc.
  • LNA is shown in formula (1)
  • ENA is shown in formula (2)
  • cET is shown in formula (3):
  • Acyclic nucleotides are a type of nucleotide formed by opening the sugar ring of a nucleotide, such as unlocked nucleic acid (UNA) or glycerol nucleic acid (GNA).
  • UNA is represented by formula (4)
  • GNA is represented by formula (4). 5
  • R is selected from H, OH or alkoxy (O-alkyl).
  • nucleotide derivative modification refers to a nucleotide in a nucleic acid being replaced with a nucleotide derivative.
  • the nucleotide derivative is selected from isonucleotides, LNA, ENA, cET, UNA or GNA.
  • nucleotides in the nucleic acid are replaced with isonucleotides, which are also referred to as isonucleoside modifications in the context of the present disclosure.
  • isonucleoside modifications include incorporating isonucleosides at one or more sites of the sense strand and/or antisense strand of the siRNA to be modified to replace natural nucleosides for coupling at the corresponding positions.
  • the isonucleoside modification adopts D-isonucleoside modification. In other embodiments, the isonucleoside modification adopts L-isonucleoside modification. In still other embodiments, the isonucleoside modification adopts D-isonucleoside modification and L-isonucleoside modification.
  • the double-stranded ribonucleic acid modification comprises modification of a phosphodiester bond at at least one position.
  • the modification of the phosphodiester bond means that at least one oxygen atom in the phosphodiester bond is replaced by a sulfur atom to form a phosphorothioate diester bond.
  • the phosphorothioate diester bond can stabilize the double-stranded structure of siRNA and maintain the specificity of base pairing.
  • An exemplary phosphorothioate diester bond structure is as follows:
  • the double-stranded ribonucleic acid modification comprises a chemical modification of at least one of the following:
  • the double-stranded ribonucleic acid modification is an siRNA modification comprising at least one chemical modification among (1)-(4).
  • sequence A in the sense strand and sequence B in the antisense strand are complementary to form a double-stranded region
  • sequence A and sequence B can be any of the following:
  • sequence A and sequence B both form blunt ends
  • sequence A has 1-2 protruding nucleotides extending out of the double-stranded region, and the 3’ end of sequence B forms a blunt end;
  • sequence B has 1-2 protruding nucleotides extending out of the double-stranded region, and the 3’ end of sequence A forms a blunt end;
  • sequence A has 1-2 protruding nucleotides extending out of the double-stranded region
  • sequence B has 1-2 protruding nucleotides extending out of the double-stranded region. Nucleotides.
  • nucleotide sequence of the sense strand is the sequence shown in Sequence A
  • nucleotide sequence of the antisense strand is the sequence shown in Sequence B.
  • the sense strand and the antisense strand are complementary to form a double-stranded region, and there are no overhanging nucleotides at the 3' ends of the sense strand and the antisense strand
  • the sense strand and the antisense strand are Add 1-2 nucleotides to the 3' end of at least one of the strands as overhanging nucleotides.
  • 1-2 nucleotides connected to the 3' end of the sense strand constitute sequence D
  • 1-2 nucleotides connected to the 3' end of the antisense strand constitute sequence E.
  • nucleotide sequence of the sense strand is sequence A connected to sequence D, and the nucleotide sequence of the antisense strand is sequence B connected to sequence E.
  • nucleotide sequence of the sense strand is the sequence represented by sequence A
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • nucleotide sequence of the sense strand is the sequence represented by sequence A connected to sequence D
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B.
  • TT deoxyribonucleotides
  • TT deoxyribonucleotides
  • nucleotide sequences of the sense strand and the antisense strand are complementary to form a double-stranded region, and there is no overhanging nucleotide at the 3' end of the sense strand, 1 is added at the 3' end of the sense strand.
  • -Sequence D consisting of 2 nucleotides as the overhanging nucleotide. Then, when the nucleotide sequence formed by connecting sequence A to sequence D is chemically modified, sequence D consisting of 1-2 nucleotides is excluded.
  • the nucleotide sequence of the sense strand is the sequence shown in sequence A
  • the nucleotide sequence of the antisense strand is the sequence shown in sequence B.
  • the nucleotide sequence of the sense strand is the sequence represented by sequence A
  • the nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • sequence A when sequence A is complementary to sequence B to form a double-stranded region, the 3' end of sequence A has 1-2 nucleotides protruding out of the double-stranded region, the protruding nucleotides at the 3' end of sequence A are excluded as the nucleotide sequence of the sense strand.
  • sequence A' The sequence excluding the protruding nucleotides at the 3' end is called sequence A'.
  • sequence A' the nucleotide sequence of the sense strand of the double-stranded RNA modified substance
  • sequence B the nucleotide sequence of the antisense strand of the double-stranded RNA modified substance
  • nucleotide sequence of the sense strand of the double-stranded RNA modified substance is the sequence shown in sequence A'
  • nucleotide sequence of the antisense strand of the double-stranded RNA modified substance is the sequence shown in sequence B connected to sequence E.
  • the sense strand of the siRNA modification includes the following modifications: the ribonucleotides at positions 7, 9, 10 and 11 in the sense strand are 2'-fluoro modified ribonucleotide; ribonucleotides at other positions in the sense strand are 2'-methoxy modified ribonucleotides.
  • the sense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and the 1st nucleotide starting from the 5' end. Between 2 nucleotides, between the 2nd nucleotide starting from the 5' end and the 3rd nucleotide, between the 1st nucleotide starting from the 3' end and the 2nd nucleotide starting from the 3' end between the 2nd and 3rd nucleotides starting from the 3' end.
  • the sense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and the 1st nucleotide starting from the 5' end. Between 2 nucleotides, between the 2nd nucleotide and the 3rd nucleotide starting from the 5' end.
  • the sense strand of the siRNA modification has a structure shown in any one of (a 1 )-(a 3 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • the sense strand of the siRNA modification has a structure shown in any one of (a 4 ) to (a 5 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • the antisense strand of the siRNA modifier includes the following modifications: the ribonucleotide at any odd position in the antisense strand is a 2'-methoxy-modified ribonucleotide, and the ribonucleotide at any even position in the antisense strand is a 2'-fluoro-modified ribonucleotide.
  • the antisense strand of the siRNA modification includes the following modifications: ribose at positions 2, 6, 14 and 16 in the antisense strand
  • the nucleotides are 2'-F modified ribonucleotides, and the remaining ribonucleotides in the antisense strand are 2'-O- CH modified ribonucleotides.
  • the antisense strand of the siRNA modification includes the following modifications: the 2nd, 6th, 8th, 9th, and 9th positions in the antisense strand.
  • the ribonucleotides at positions 14 and 16 are 2'-F modified ribonucleotides, and the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides. .
  • the ribonucleotides at positions 2, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides
  • the ribonucleotide at position 6 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense strand are modified with 2'-O-CH 3 of ribonucleotides.
  • the antisense strand of the siRNA modification includes the following modifications: ribose at positions 2, 6, 14 and 16 in the antisense strand
  • the nucleotide is a 2'-F modified ribonucleotide
  • the ribonucleotide at position 7 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA
  • the ribonucleotide at position is a 2'-O-CH 3 modified ribonucleotide.
  • the antisense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and Between the 2nd nucleotide, between the 2nd nucleotide and the 3rd nucleotide starting from the 5' end, between the 1st nucleotide and the 2nd nucleotide starting from the 3' end between the 2nd and 3rd nucleotides starting from the 3' end.
  • the nucleotide at the 5' end of the antisense strand is connected to a 5' phosphate group or a 5' phosphate derivative group along the 5' end to the 3' end.
  • the structure of the 5' phosphate group is:
  • the structures of the 5' phosphate derivative group include but are not limited to: wait.
  • the siRNA modification antisense strand has the structure shown in any one of the following (b 1 )-(b 15 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide indicates that the adjacent nucleotide on the right side of the letter is a 5'-phosphate nucleotide, -(s)- indicates that the two adjacent nucleotides are connected by a phosphorothioate diester bond , [GNA] indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified by GNA.
  • the sense strand includes the nucleotide sequence shown in any one of SEQ ID NO:309 ⁇ 342 and SEQ ID NO:448 ⁇ 470
  • the antisense strand includes the nucleotide sequence shown in any one of SEQ ID NO:309 ⁇ 342 and SEQ ID NO:448 ⁇ 470.
  • double-stranded ribonucleic acid modifications include, but are not limited to, siRNA modifications as shown in Table 2.
  • the third aspect of the present disclosure provides a double-stranded ribonucleic acid conjugate, which is obtained by conjugating the double-stranded ribonucleic acid provided by the first aspect of the present disclosure or the double-stranded ribonucleic acid modification provided by the second aspect and a conjugation group. .
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate form a double-stranded region of the double-stranded ribonucleic acid conjugate, and are formed at the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate.
  • Flat ends In some embodiments, the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate forms a blunt end and the 3' end of the antisense strand of the double-stranded ribonucleic acid conjugate has 1-2 extensions out of the duplex. overhanging nucleotides in the region.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate forms a blunt end
  • the 3' end of the antisense strand of the double-stranded ribonucleic acid conjugate forms a blunt end
  • the double-stranded ribonucleic acid conjugate is obtained by conjugating a double-stranded ribonucleic acid modification with a conjugating group.
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid modification are complementary to form the double-stranded region of the double-stranded ribonucleic acid modification, and the 3' end of the sense strand of the double-stranded ribonucleic acid modification forms a blunt end, and the conjugation group The group is conjugated to the 3' end of the sense strand with a blunt end to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product is blunt-ended, and the 3' end of the sense strand of the double-stranded ribonucleic acid modified product is connected to a conjugation group to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product forms a blunt end
  • a conjugation group is connected to the 3' end of the sense strand of the double-stranded ribonucleic acid modified product to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A connected to sequence D
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product has a protruding sequence D consisting of 1-2 nucleotides. After excluding the sequence D at the 3' end of the sense strand of the double-stranded ribonucleic acid modified product, A conjugation group is connected to the 3' end of sequence A to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded RNA modification is a sequence shown by sequence A connected to sequence D
  • the antisense strand is a sequence shown by sequence B.
  • the 3' end of the sense strand of the double-stranded RNA modification has a sequence D consisting of 1-2 nucleotides protruding, and after excluding the sequence D at the 3' end of the sense strand in the double-stranded RNA modification, a conjugation group is connected to the 3' end of sequence A to form a double-stranded RNA conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of sequence A has a protruding nucleotide extending out of the double-stranded region, and the sequence after excluding the protruding nucleotide located at the 3' end of sequence A (also called sequence A') is used.
  • sequence A' The nucleotide sequence to which the conjugation group is attached.
  • nucleotide sequence of the sense strand of the double-stranded ribonucleic acid conjugate is the sequence represented by sequence A'
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B.
  • the 3' end of sequence A has a protruding nucleotide extending out of the double-stranded region, and the sequence after excluding the protruding nucleotide located at the 3' end of sequence A (also called sequence A') is used.
  • sequence A' The nucleotide sequence to which the conjugation group is attached. Therefore, the nucleotide sequence of the sense strand of the double-stranded ribonucleic acid conjugate is the sequence shown in sequence A', and the nucleotide sequence of the antisense strand is the sequence shown in sequence B.
  • the sense strand of the double-stranded ribonucleic acid conjugate has a structure shown in any one of (d 1 )-(d 2 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • L96 is also the conjugate group GalNAc shown in formula I.
  • the antisense strand of the double-stranded ribonucleic acid conjugate has a structure shown in any one of (b 1 )-(b 15 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide indicates that the adjacent nucleotide on the right side of the letter is a 5'-phosphate nucleotide, -(s)- indicates that the two adjacent nucleotides are connected by a phosphorothioate diester bond , [GNA] indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified by GNA.
  • the double-stranded ribonucleic acid conjugate is an siRNA conjugate, wherein the siRNA molecule connected to the conjugation group in the siRNA conjugate can be unmodified siRNA or siRNA modification.
  • siRNA molecules modified with conjugation groups also have better tissue and organ targeting and the ability to promote cell endocytosis, which can reduce the impact on other tissues or organs.
  • the purpose of reducing toxicity and reducing costs can be achieved.
  • select any siRNA molecule shown in Table 1 or Table 1-1 or Table 2 and connect it to a conjugation group to obtain a double-stranded ribonucleic acid conjugate.
  • the conjugation site of siRNA and the conjugation group can be at the 3’ end or 5’ end of the sense strand of siRNA, or at the 5’ end of the antisense strand, or in the internal sequence of siRNA. In some embodiments, the conjugation site of the siRNA and the conjugation group is at the 3' end of the sense strand of the siRNA.
  • the conjugation group can be attached to the phosphate group, the 2'-hydroxyl group, or the base of the nucleotide. In some embodiments, the conjugation group can also be connected to the 3'-position hydroxyl group, in which case the nucleotides are connected via a 2', 5'-phosphodiester bond.
  • the conjugation group is usually attached to the phosphate group of the nucleotide; when the conjugation group is attached to the internal sequence of the siRNA, the conjugation group Usually attached to the ribose sugar ring or base.
  • the conjugating group may be a ligand commonly used in the field of siRNA delivery.
  • the conjugation group can be selected from one or more ligands formed by the following targeting molecules or derivatives thereof: lipophilic molecules, such as cholesterol, bile acids, vitamins (such as vitamin E ), lipid molecules of different chain lengths; polymers, such as polyethylene glycol; peptides, such as membrane-penetrating peptides; aptamers; antibodies; quantum dots; sugars, such as lactose, polylactose, mannose, galactose, N-acetylgalactosamine (GalNAc); folate; receptor ligands expressed by liver parenchymal cells, such as asialoglycoprotein, asialoglycoside residues, lipoproteins (such as high-density lipoprotein, low-density lipoprotein) Lipoproteins, etc.), glucagon, neurotransmitters (such as epinephrine), glucagon, neuro
  • the conjugation group has the structure shown below:
  • GalNAc has liver-targeting properties and can deliver siRNA molecules to liver tissue with high specificity and specifically inhibit the high expression of HMGB1 gene in the liver.
  • GalNAc is conjugated to the 3' end of the sense strand through a phosphodiester bond, resulting in an siRNA conjugate with the following structure:
  • the double helix structure is unmodified siRNA or siRNA modification.
  • double-stranded ribonucleic acid conjugates include, but are not limited to, siRNA conjugates as shown in Table 3.
  • the fourth aspect of the present disclosure provides a pharmaceutical composition, including the double-stranded ribonucleic acid described in the first aspect, the double-stranded ribonucleic acid modification described in the second aspect, and the double-stranded ribonucleic acid conjugate described in the third aspect. one or more of the compounds.
  • the pharmaceutical composition contains siRNA as described above as an active ingredient and a pharmaceutically acceptable carrier.
  • the purpose of using pharmaceutical compositions is to promote administration to living organisms, facilitate the absorption of active ingredients, and thereby exert biological activity.
  • the pharmaceutical compositions of the present disclosure can be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid formulation, oral liquid formulation), rectal, inhalation, implantation , local (such as eye) administration, etc.
  • oral solid preparations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like.
  • Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like.
  • Non-limiting examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, agents or serum preparations.
  • Non-limiting examples of parenteral formulations include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like.
  • the pharmaceutical compositions of the present disclosure may also be formulated into controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • the route of administration can be varied or adjusted in any applicable manner to meet the requirements of the properties of the drug, the convenience of the patient and the medical staff, and other relevant factors.
  • a fifth aspect of the present disclosure provides at least one of the following uses of double-stranded ribonucleic acid, double-stranded ribonucleic acid modifications or double-stranded ribonucleic acid conjugates:
  • the present disclosure further provides the use of siRNA molecules (including unmodified siRNA, siRNA modifications, siRNA conjugates) or pharmaceutical compositions in at least one of the above (1)-(3).
  • abnormal expression of HMGB1 gene causes one or more of the following diseases related to abnormal expression of HMGB1 gene: non-alcoholic steatohepatitis, sepsis, arthritis, colitis, acute lung injury, colorectal cancer, and gastric cancer , myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, lymphoma, multiple myeloma and atherosclerosis, etc.
  • the siRNA molecule causes the expression of the HMGB1 gene to be inhibited by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least About 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least About 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, achieve abnormal expression of the HMGB1 gene Treatment of related diseases.
  • the present disclosure provides a method of inhibiting HMGB1 gene expression in a cell, comprising contacting a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition with the cell.
  • a method to inhibit the expression of HMGB1 gene in cells is to introduce siRNA molecules (including unmodified siRNA, siRNA modifications, siRNA conjugates) or pharmaceutical compositions into cells.
  • the cells are in vivo cells or in vitro cells. In some specific embodiments, the cells are in a subject.
  • the present disclosure provides methods of preventing or treating disease, comprising administering a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition to a subject.
  • the method for preventing or treating a disease is to administer siRNA molecules (including unmodified siRNA, siRNA modifications, siRNA conjugates) or pharmaceutical compositions to a subject.
  • subject includes either a human or a non-human animal, preferably a vertebrate, and more preferably a mammal.
  • the subject may include a transgenic organism. Most preferably, the subject is a human. Further, the subject has at least one of the following characteristics:
  • the capital letters "G”, “C”, “A”, “T” and “U” in the above table each generally represent nucleosides containing guanine, cytosine, adenine, thymine and uracil as bases respectively.
  • the two adjacent nucleotides on the left and right are connected by a phosphorothioate group; P1: indicates that the nucleotide adjacent to the right of P1 is a 5'-phosphate nucleotide, and [GNA] indicates the phase on the right.
  • the adjacent ribonucleotide is a ribonucleotide modified with GNA.
  • the experimental techniques and experimental methods used in this example are all conventional technical methods unless otherwise specified.
  • the experimental methods without specifying specific conditions in the following examples usually follow conventional conditions, such as Sambrook et al., Molecular Cloning: Experiment The conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or the conditions recommended by the manufacturer.
  • the materials, reagents, etc. used in the examples can be obtained through regular commercial channels unless otherwise specified.
  • siRNA, siRNA modifications, and siRNA conjugates involved in the following examples were synthesized by Tianlin Biotechnology (Shanghai) Co., Ltd.
  • the cells and reagents used in the examples are shown in Table 4:
  • HMGB1 siRNAs Based on the human HMGB1 gene mRNA sequence, multiple pairs of HMGB1 siRNAs were designed at different sites. All single siRNAs designed can target all transcripts of the target gene (as shown in Table 5). These multiple pairs of siRNAs were compared with other pairs by sequence similarity software. All non-target gene sequences have minimal homology.
  • the target sequence used to design siRNA is as follows.
  • the target sequence is derived from the HMGB1 gene mRNA sequence (see NM_002128.7).

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Abstract

La présente invention concerne un acide ribonucléique double brin (ARN) pour inhiber l'expression du gène HMGB1, et un modificateur, un conjugué et une utilisation de celui-ci. Plus particulièrement, la présente invention concerne un ARN double brin pour inhiber l'expression du gène HMGB1, un modificateur d'ARN double brin, un conjugué d'ARN double brin, une composition pharmaceutique, une utilisation et un procédé pour inhiber l'expression intracellulaire du gène HMGB1. L'ARN double brin procuré par la présente invention peut être combiné dans les cellules pour constituer un complexe de suppresssion de l'expression induite par l'ARN (RISC), coupe l'ARNm transcrit par un gène HMGB1, inhibe efficacement et particulièrement l'expression du gène HMGB1, est utilisé pour traiter les maladies médiées par le gène HMGB1, et présente d'importantes perspectives d'application dans le traitement clinique des maladies.
PCT/CN2023/119654 2022-09-20 2023-09-19 Acide ribonucléique double brin pour l'inhibition de l'expression du gène hmgb1, et modificateur, conjugué et son utilisation Ceased WO2024061202A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN111050776A (zh) * 2017-06-29 2020-04-21 迪克纳制药公司 用于抑制hmgb1表达的组合物和方法
WO2020139764A1 (fr) * 2018-12-28 2020-07-02 Dicerna Pharmaceuticals, Inc. Compositions et procédés d'inhibition de l'expression de hmgb1
CN111727252A (zh) * 2017-12-18 2020-09-29 阿尔尼拉姆医药品有限公司 高速泳动族盒-1（HMGB1）iRNA组合物及其使用方法

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CN111050776A (zh) * 2017-06-29 2020-04-21 迪克纳制药公司 用于抑制hmgb1表达的组合物和方法
CN111727252A (zh) * 2017-12-18 2020-09-29 阿尔尼拉姆医药品有限公司 高速泳动族盒-1（HMGB1）iRNA组合物及其使用方法
WO2020139764A1 (fr) * 2018-12-28 2020-07-02 Dicerna Pharmaceuticals, Inc. Compositions et procédés d'inhibition de l'expression de hmgb1

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