WO2024255747A1 - Acide nucléique ciblant le composant 5 du complément et son utilisation - Google Patents

Acide nucléique ciblant le composant 5 du complément et son utilisation Download PDF

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WO2024255747A1
WO2024255747A1 PCT/CN2024/098563 CN2024098563W WO2024255747A1 WO 2024255747 A1 WO2024255747 A1 WO 2024255747A1 CN 2024098563 W CN2024098563 W CN 2024098563W WO 2024255747 A1 WO2024255747 A1 WO 2024255747A1
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nucleotides
nucleotide
nucleic acid
sequence
disease
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蒋伟文
郁东
兰涛
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Synerk Pharmatech Suzhou Ltd
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Synerk Pharmatech Suzhou Ltd
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Definitions

  • the present invention relates to the field of biotechnology, in particular to a nucleic acid targeting complement component 5 and uses thereof.
  • Complement component 5 is a 188kDa protein expressed in hepatocytes (Tack BF et al.).
  • C5 is one of the complements in the human blood complement system and can be activated by three complement activation pathways: the classical activation pathway, the alternative activation pathway, and the lectin activation pathway. After activation, C5 is cleaved into C5a and C5b by C5 convertase.
  • C5a is a chemotactic factor for neutrophils, while C5b can form a membrane attack complex, causing cell membrane damage (Merle NS et al.; DiScipio RG).
  • C5 deficiency may lead to recurrent infections.
  • Activation of the complement system can also lead to a variety of autoimmune diseases.
  • RNA interference refers to a highly conserved gene that is produced by Double-stranded small interfering RNA (siRNA) induces efficient and specific degradation of homologous mRNA. RNAi drugs also have the advantage of longer efficacy than antibodies. Therefore, it is of great significance to study and develop siRNA targeting C5.
  • the purpose of the present invention is to overcome the problems existing in the prior art and provide a novel nucleic acid targeting complement component 5 and its use.
  • the first aspect of the present invention provides a nucleic acid, which includes a sense chain and an antisense chain, wherein the sense chain contains a sequence having more than 80% sequence identity with the sequence shown in any one of SEQ ID NOs: 1 to 34, and the antisense chain contains a sequence having more than 80% sequence identity with the sequence shown in any one of SEQ ID NOs: 35 to 68.
  • a second aspect of the present invention provides a targeted drug delivery system, which comprises a targeting group, a linking group, and the nucleic acid as described above connected to the targeting group via the linking group.
  • the third aspect of the present invention provides a pharmaceutical composition, which contains the nucleic acid or targeted drug delivery system as described above and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a method for inhibiting the expression of complement component 5 gene in a cell, the method comprising: contacting the cell with the nucleic acid, targeted drug delivery system or pharmaceutical composition as described above to inhibit the expression of complement component 5 gene in the cell.
  • the fifth aspect of the present invention provides the use of the nucleic acid, targeted drug delivery system or pharmaceutical composition as described above in any of the following aspects: 1) treating and/or preventing diseases associated with complement component 5; 2) preparing drugs for treating and/or preventing diseases associated with complement component 5.
  • the nucleic acid of the present invention can effectively reduce the level of C5, and can effectively prevent or treat complement system-related diseases, such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, systemic myasthenia gravis, neuromyelitis optica, systemic lupus erythematosus, etc.
  • complement system-related diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, systemic myasthenia gravis, neuromyelitis optica, systemic lupus erythematosus, etc.
  • FIG. 1 shows the C5 protein level in serum on the fourth day after injection of siRNA drug in an embodiment of the present invention.
  • FIG. 2 is a comparison of the effects of the siRNA drug in the embodiment of the present invention and the existing SN-68002.
  • FIG3 shows the efficacy of SN-681263 and SN-681274 in human C5 transgenic mice according to the examples of the present invention.
  • FIG. 4 shows the efficacy of siRNA in human C5 transgenic mice according to an embodiment of the present invention; wherein A is the experimental result of SN-681263; and B is the experimental result of SN-681274.
  • the technical solution of "A, and/or, B, and/or, C, and/or, D” includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").
  • the present invention relates to concentration values, and its meaning includes fluctuations within a certain range. For example, it can fluctuate within the corresponding accuracy range. For example, 2% can allow fluctuations within the range of ⁇ 0.1%. For values that are large or do not require too fine control, its meaning is also allowed to include greater fluctuations. For example, 100mM can allow fluctuations within the range of ⁇ 1%, ⁇ 2%, ⁇ 5%, etc. Involving molecular weight, its meaning is allowed to include fluctuations of ⁇ 10%.
  • the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.
  • nucleic acid refers to a composition containing RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecules, which can degrade or inhibit (e.g., degrade or inhibit under appropriate conditions) the translation of messenger RNA (mRNA) transcripts of target mRNA in a sequence-specific manner.
  • the nucleic acid can act through an RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway mechanism of mammalian cells (RNA-induced silencing complex or RISC)), or through any alternative mechanism or approach.
  • RNA interference mechanism i.e., inducing RNA interference through interaction with the RNA interference pathway mechanism of mammalian cells (RNA-induced silencing complex or RISC)
  • nucleic acids disclosed herein including sense and antisense strands includes, but is not limited to, short (or small) interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), short hairpin RNA (shRNA) and dicer substrates.
  • siRNA short (or small) interfering RNA
  • dsRNA double-stranded RNA
  • miRNA microRNA
  • shRNA short hairpin RNA
  • the terms “silencing”, “reducing”, “inhibiting”, “downregulating” or “knockdown” when referring to the expression of a given gene mean that the expression of the gene is reduced when the cell, cell population, tissue, organ or subject is treated with a nucleic acid described herein, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein or protein subunit translated from mRNA in a cell, cell population, tissue, organ or subject in which the gene is transcribed, compared to a second cell, cell population, tissue, organ or subject not so treated.
  • "fully complementary” means that in a hybridization pair of nucleobase or nucleotide sequence molecules, all (100%) bases in the contiguous sequence of the first oligonucleotide hybridize with the same number of bases in the contiguous sequence of the second oligonucleotide.
  • the contiguous sequence may include all or part of the first nucleotide sequence or the second nucleotide sequence.
  • substantially complementary means that in a hybridization pair of nucleobase or nucleotide sequence molecules, At least 70%, but not all, of the bases in the contiguous sequence of the first oligonucleotide hybridize to the same number of bases in the contiguous sequence of the second oligonucleotide.
  • the contiguous sequence may comprise all or part of the first nucleotide sequence or the second nucleotide sequence.
  • substantially complementary means that in a hybridization pair of nucleobase or nucleotide sequence molecules, at least 85% but not all of the bases in the contiguous sequence of the first oligonucleotide hybridize with the same number of bases in the contiguous sequence of the second oligonucleotide.
  • the contiguous sequence may comprise all or part of the first nucleotide sequence or the second nucleotide sequence.
  • "at least partially complementary” means that the first oligonucleotide and the second oligonucleotide are partially complementary, substantially complementary or completely complementary in a hybridization pair of nucleobase or nucleotide sequence molecules.
  • the term "treatment” means a method or step taken to provide relief or reduction in the number, severity and/or frequency of one or more disease symptoms in a subject.
  • the treatment may include prevention, management, prophylactic treatment, and/or inhibition or reduction of the number, severity and/or frequency of one or more disease symptoms in a subject.
  • connection means that two compounds or molecules are joined by a covalent bond. Unless otherwise specified, as used herein, the term “connection” may refer to a connection between a first compound and a second compound with or without any intermediate atoms or atomic groups.
  • the present invention provides a (modified or unmodified) nucleic acid, which comprises a sense strand and an antisense strand, wherein the sense strand comprises a sequence having a sequence identity of 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) or more to any one of SEQ ID NOs: 1 to 34, and the antisense strand comprises a sequence having a sequence identity of 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) or more to any one of SEQ ID NOs: 35 to 68.
  • the sense strand comprises a sequence having a sequence identity of 80% (e
  • the antisense strand has 15 to 30 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) nucleotides (bases).
  • the sense strand has 15 to 30 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) nucleotides (bases).
  • nucleic acid RNA
  • the nucleic acid is selected from at least one of siRNA-1 whose sense chain sequence is SEQ ID NO: 1 and whose antisense chain sequence is SEQ ID NO: 35, siRNA-2 whose sense chain sequence is SEQ ID NO: 2 and whose antisense chain sequence is SEQ ID NO: 36, siRNA-3 whose sense chain sequence is SEQ ID NO: 3 and whose antisense chain sequence is SEQ ID NO: 37, siRNA-4 whose sense chain sequence is SEQ ID NO: 4 and whose antisense chain sequence is SEQ ID NO: 38, siRNA-5 whose sense chain sequence is SEQ ID NO: 5 and whose antisense chain sequence is SEQ ID NO: 39..., siRNA-32, siRNA-33, and siRNA-34.
  • the antisense strand contains at least 15, 16, 17, 18, 19, 20, 21, 22 or 23 consecutive nucleotides that differ from the sequence shown in any one of SEQ ID NOs: 35 to 68 by no more than 0, 1, 2 or 3 nucleotides
  • the positive strand contains a nucleotide sequence that is at least partially complementary (such as partially complementary, substantially complementary or completely complementary) to the antisense strand.
  • the positive strand contains at least 15, 16, 17, 18, 19, 20 or 21 consecutive nucleotides that differ from the sequence shown in any one of SEQ ID NOs: 1 to 34 by no more than 0, 1, 2 or 3 nucleotides.
  • the sense strand and the antisense strand may have the same length or different lengths.
  • nucleotide groups in the above nucleic acid may be chemically unmodified, or may contain at least one modified nucleotide group, and the modification may be on the nucleotide at any position.
  • the sense strand and antisense strand may be partially complementary to each other, substantially Complementary or completely complementary.
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in any one of SEQ ID NOs: 35, 36, 37, 38, 39, 41, and 43 by 0, 1, or 2 nucleotides
  • the sense strand contains a nucleotide sequence that is at least partially complementary (such as partially complementary, substantially complementary, or completely complementary) to the antisense strand.
  • the antisense strand has the above sequence, the double-stranded RNA has a significantly better inhibitory effect on C5.
  • the positive chain contains a nucleotide sequence that differs by 0, 1 or 2 nucleotides from the sequence shown in any one of SEQ ID NO: 1, 2, 3, 4, 5, 7, 9.
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in any one of SEQ ID NOs: 35 and 36 by 0, 1 or 2 nucleotides, and the sense strand contains a nucleotide sequence that is at least partially complementary (such as partially complementary, substantially complementary or completely complementary) to the antisense strand.
  • the antisense strand has this sequence, the inhibitory effect of double-stranded RNAs with different modifications on C5 is further improved.
  • the positive chain contains a nucleotide sequence that differs from the sequence shown in any one of SEQ ID NO: 1, 2 by 0, 1 or 2 nucleotides.
  • the antisense strand contains a nucleotide sequence that differs from the sequence shown in SEQ ID NO: 36 by 0, 1 or 2 nucleotides, and the sense strand contains a nucleotide sequence that is at least partially complementary (such as partially complementary, substantially complementary or completely complementary) to the antisense strand.
  • the antisense strand has this sequence, the inhibitory effect of double-stranded RNAs with different modifications on C5 is optimal.
  • the positive strand contains a nucleotide sequence that differs by 0, 1 or 2 nucleotides from the sequence shown in any one of SEQ ID NO: 2.
  • sequence identity of the sense strand or antisense strand in the nucleic acid with the corresponding sequence mentioned in the present invention when the sequence identity of the sense strand or antisense strand in the nucleic acid with the corresponding sequence mentioned in the present invention is less than 100% or differs by more than 1 nucleotide, it still has a similar or equivalent inhibitory effect on C5 as the corresponding sequence.
  • the UU connected to the 3' end is replaced by AA, CC, GG or UG, etc., or a combination of any two nucleic acids.
  • Such nucleic acid sequences also fall within the protection scope of the present invention.
  • the nucleic acid contains a nucleotide group as a basic structural unit, and the nucleotide group contains a phosphate group, a ribose group and a base.
  • the nucleic acid contains at least one modified nucleotide group.
  • the inhibition efficiency of the modified nucleic acid on C5 is not less than 50% (such as 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% or 99%).
  • the modified nucleotide group is a nucleotide group in which a phosphate group and/or a ribose group is modified.
  • the modified site can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 of the 1st, 2nd, 3rd, 4th, 5th, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30th nucleotide of the sense strand and/or the antisense strand.
  • modification of the phosphate group refers to modification of the oxygen in the phosphate group, including phosphorothioate modification and boranophosphate modification.
  • the oxygen in the phosphate group is replaced by sulfur, borane, amine, alkyl or alkoxy.
  • BASE represents the base A, U, C, G or T.
  • X can be oxygen (O) or sulfur (S).
  • R in the above structure can be the same or different, such as: hydrogen (H), fluorine (F), methoxy (OME) or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, amino, cyanoethyl, acetyl, etc.
  • R' and R" can each independently be hydrogen (H), methyl (CH3), ethyl (CH2CH3), propyl (CH2CH2CH3), isopropyl (CH(CH3)2), allyl, propargyl, acyloxybenzyl, acyloxyethyl.
  • the modification of the ribose group refers to the modification of the 2′-hydroxyl (2′-OH) in the ribose group.
  • the modification of the 2′-hydroxyl in the pentose of nucleotides includes 2′-fluoro modification (2′-fluoromodification, such as 2′-arabino-fluoro modification), 2′-methoxy modification (2′-OME), 2′-methoxyethyl modification (2′-MOE), 2′-2,4-dinitrophenol modification (2′-DNP modification), cyclolocked ethyl modification (2′,4′-constrained ethyl modification), 2'-Amino modification, 2'-deoxy modification, BNA, acyclic nucleic acid modification, misplaced nucleic acid modification, L-type nucleic acid modification, etc.
  • 2′-fluoromodification such as 2′-arabino-fluoro modification
  • 2′-OME 2′-methoxyethyl modification
  • 2′-MOE 2′-2,4-dinitrophenol modification
  • cyclolocked ethyl modification (2′,4′-constrained e
  • BNA endocyclic bridged nucleotide refers to a constrained or inaccessible nucleotide.
  • BNA can contain a five-membered ring, a six-membered ring, or a seven-membered ring with a "fixed" C 3'-endo sugar condensed bridge structure.
  • the bridge is usually incorporated into the 2'-, 4'-position of the ribose ring to provide a 2', 4'-BNA nucleotide, such as locked ethyl modification (LNA), ring locked ethyl modification (ENA) and ethyl locked nucleic acid modification (cET BNA).
  • LNA locked ethyl modification
  • ENA ring locked ethyl modification
  • cET BNA ethyl locked nucleic acid modification
  • Acyclic nucleic acids are nucleotides formed by opening the sugar ring of the nucleotide, such as unlocked nucleic acid (UNA) nucleotides and glycerol nucleic acid (GNA) nucleotides.
  • Unlocked nucleic acid (UNA) nucleotides and glycerol nucleic acid (GNA) nucleotides are nucleotides formed by opening the sugar ring of the nucleotide, such as unlocked nucleic acid (UNA) nucleotides and glycerol nucleic acid (GNA) nucleotides.
  • Misplaced nucleic acid modification refers to the replacement of the 3', 5'-phosphate bond link by a 2', 5'-phosphate bond chain.
  • L-type nucleic acid modification refers to the replacement of the naturally occurring D-type nucleic acid with its mirror stereo equivalent L-type nucleic acid.
  • BASE represents the base A, U, C, G or T.
  • R in the above structure can be the same or different, such as: hydrogen (H), fluorine (F), methoxy (OME) or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, cyanoethyl, acetyl, etc.
  • the nucleotide group in which the ribose group is modified is a nucleotide group in which the 2'-OH of the ribose group is substituted by a methoxy group or a fluorine group.
  • the nucleotide group containing uracil base or cytosine base in the sense strand of the nucleic acid is a nucleotide group in which the ribose group is modified, that is, the nucleotide group containing uracil base or cytosine base in the sense strand of the nucleic acid
  • the 2'-OH of the ribose group in the nucleic acid is replaced by a methoxy group or a fluorine group.
  • the 3' end of the sense strand and the antisense strand of the nucleic acid can be connected to dTdT; or, the 3' end of the antisense strand of the nucleic acid can be connected to AA or UU or a combination of any two nucleic acids (which can be but is not limited to CC, GG or UG), so that the sequence has a specific inducement to mRNA degradation.
  • the nucleic acid with the above modifications shows a more excellent in vivo inhibitory effect, and the above modifications can further reduce the immunogenicity of the nucleic acid of the present invention in vivo.
  • the nucleic acid of the present invention may also include a modification of a monophosphate nucleoside connected to the 5' end of the antisense strand. Since the 5'-monophosphate at the terminal of the siRNA guide strand is important for RISC recognition. Among them, the phosphorylation of the 5'-hydroxyl group plays a certain role in whether the siRNA can be effectively loaded into the Ago2 inside the cell.
  • the 5'-terminal monophosphate of the guide strand in the siRNA has an H bond interaction with Argonaute-2 (Ago2), thereby ensuring accurate positioning and precise cutting of the mRNA target.
  • Ago2 Argonaute-2
  • phosphate nucleoside derivatives have been proven to have certain stability in biological metabolic media and have a certain effect on promoting the loading of the siRNA guide strand into the Ago2 inside the cell (Nucleic Acids Research, 2015, 43, 2993-3011).
  • trans-vinyl phosphate (VP) is the first choice
  • monophosphate nucleoside derivatives other than those described above may also be included.
  • BASE represents the base A, U, C, G or T.
  • R in the above structure can be the same or different, such as hydrogen (H), fluorine (F), methoxy (OME) Or methoxyethyl (MOE), hydroxyl, allyl, ethylamino, propargyl, cyanoethyl, amino, acetyl, etc.
  • At least one nucleotide in the nucleic acid is a modified nucleotide or includes a modified linkage.
  • the modified nucleotide is selected from one or more of 2'-O-methyl nucleotides, 2'-fluoro nucleotides, 2'-deoxy nucleotides, 2',3'-open ring nucleotide mimics, locked nucleotides, 2'-F-arabino nucleotides, 2'-methoxyethyl nucleotides, abasic nucleotides, ribitols, reverse nucleotides, reverse 2'-O-methyl nucleotides, reverse 2'-deoxy nucleotides, 2'-amino modified nucleotides, 2'-alkyl modified nucleotides, morpholino nucleotides, nucleotides containing vinyl phosphonate, nucleotides containing cyclopropyl phosphonate and 3'-O-methyl nucleotides; the modified nucleotide is further preferably selected from one or more of 2'-O-methyl
  • the modified inter-linkage is preferably selected from one or more of phosphorothioate inter-nucleotide linkages and methylphosphonate inter-nucleotide linkages; the modified inter-linkage is further preferably selected from one or more of phosphorothioate monoester inter-nucleotide linkages and phosphorothioate diester inter-nucleotide linkages.
  • the antisense strand contains two phosphorothioate internucleotide bonds at the 5' end and the 3' end, respectively, and contains 4 to 6 2'-fluoro nucleotides, and the remaining nucleotides are 2'-O-methyl nucleotides.
  • the 5' end of the sense strand contains two phosphorothioate internucleotide bonds and 2 to 4 2'-fluoro nucleotides, and the remaining nucleotides are all 2'-O-methyl nucleotides.
  • the antisense strand has 2'-fluoro nucleotides at the 2nd, 4th, 6th, 14th and 16th nucleotides counted from the 5' end.
  • the sense strand has 2'-fluoro nucleotides at the 7th, 9th and 11th nucleotides counted from the 5' end.
  • the antisense strand has at least 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 4 18, 19, 20, 21, 22 or 23 consecutive nucleotides, the sense strand having at least 15, 16, 17, 18, 19, 20 or 21 consecutive nucleotides that differ from the sense strand sequence of any one of Table 2 by no more than 0, 1, 2 or 3 nucleotides.
  • the sense strand and the antisense strand form a siRNA having any one of the sequences shown in Table 3.
  • the antisense strand contains a nucleotide sequence from the 5' end to the 3' end that differs from the following nucleotide sequence by 0, 1 or 2 nucleotides:
  • the sense strand contains a nucleotide sequence that is at least partially complementary to the antisense strand.
  • the sense strand contains a nucleotide sequence from the 5' end to the 3' end that differs by 0, 1 or 2 nucleotides from any of the following nucleotide sequences:
  • SN-21274 gscsaaacAfgCfaAfugcaaaacac;
  • the antisense strand contains a nucleotide sequence from the 5' end to the 3' end that differs from the following nucleotide sequence by 0, 1 or 2 nucleotides:
  • the sense strand contains a nucleotide sequence that is at least partially complementary to the antisense strand.
  • SN-21274 gscsaaacAfgCfaAfugcaaaacac.
  • those skilled in the art can combine the sense strand and antisense strand sequences mentioned above in consideration of the complementarity of the sense strand and the antisense strand.
  • the sense strand and antisense strand sequences with the same last three digits of the number are combined to obtain the corresponding nucleic acid (siRNA).
  • SN-21263 and SN-51263 are combined, and SN-21274 and SN-51274 are combined to obtain the corresponding nucleic acid (siRNA).
  • the nucleic acid according to the present invention can be obtained by conventional methods in the art, such as solid phase synthesis and liquid phase synthesis, and the solid phase synthesis has commercial custom services and can therefore be obtained commercially.
  • the modified nucleotide group can be introduced by a nucleotide monomer having a corresponding modification.
  • the present invention can further construct an shRNA expression plasmid having the same or similar function as the above siRNA.
  • the method for constructing the expression plasmid is well known to those skilled in the art and will not be described in detail here.
  • the present invention also provides a targeted gene site of the nucleic acid as described above.
  • the targeted gene site is marked as any one of the items in column 1 of Table 1.
  • the first column refers to the position of the first base of the targeted gene in the C5 gene sequence, and so on; the numbers in the third and fifth columns represent the sequence numbers, for example, "1" represents SEQ ID NO: 1.
  • the reference sequence of the targeted gene is the coding sequence of human complement component 5 NM_001317163.2.
  • the present invention also provides a targeted drug delivery system, characterized in that the targeted drug delivery system comprises a targeting group, a linking group and the nucleic acid as described above connected to the targeting group via the linking group.
  • nucleic acid (siRNA) of the present invention has a better inhibitory effect when applied to different targeted drug delivery systems.
  • the naked sequence and modified sequence that are intended to be protected in the present invention do not rely on the selection of the targeting vector for their effect.
  • the present invention also optimizes the targeted drug delivery system and obtains the following technical scheme.
  • the linker is linked to the 3' end or the 5' end of the sense strand or the antisense strand of the nucleic acid.
  • the linker is attached to the 3' end of the sense strand of the nucleic acid.
  • the targeted drug delivery system comprises a ligand and the nucleic acid linked to the ligand.
  • the ligand is a GalNAc derivative.
  • the ligand is one or more GalNAc derivatives connected by single-stranded, double-stranded, or triple-stranded branched linkers.
  • the structure of the targeted drug delivery system is shown in Formula I below:
  • Nu represents the nucleic acid (siRNA).
  • the compound part in the system can be connected to the 5' end or 3' end of the sense strand of the siRNA through a phosphodiester bond, and can also be connected to the 5' end or 3' end of the antisense strand of the siRNA through a phosphodiester bond.
  • the targeted drug delivery system utilizes the structural characteristics on its left side to improve the cell penetration ability of the nucleic acid drug (Nu), enhance its stability in the cell, and has a simple preparation process and strong practicality.
  • the present invention also provides a pharmaceutical composition, which contains the nucleic acid or targeted drug delivery system as described above and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be prepared from the nucleic acid and the pharmaceutically acceptable carrier by conventional methods.
  • the pharmaceutical composition can be an injection.
  • the injection can be used for subcutaneous, intramuscular or intravenous injection.
  • the content of the pharmaceutically acceptable carrier can be 1-100000 parts by weight (such as 1 part by weight, 5 parts by weight, 10 parts by weight, 50 parts by weight, 100 parts by weight, 500 parts by weight, 1000 parts by weight, 5000 parts by weight, 10000 parts by weight, 50000 parts by weight, 100000 parts by weight or any value between any two of the above values).
  • the pharmaceutically acceptable carrier can be various carriers conventionally used in the art, for example, it can include at least one of a pH buffer, a protective agent and an osmotic pressure regulator.
  • the pH buffer can be a tris(hydroxymethyl)aminomethane hydrochloride buffer with a pH value of 7.5-8.5 and/or a phosphate buffer with a pH value of 5.5-8.5, preferably a phosphate buffer with a pH value of 5.5-8.5.
  • the protective agent can be at least one of inositol, sorbitol and sucrose.
  • the content of the protective agent can be 0.01-30% by weight (such as 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.5% by weight, 1% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight or any value between any two of the above values).
  • the osmotic pressure regulator can be sodium chloride and/or potassium chloride.
  • the content of the osmotic pressure regulator makes the osmotic pressure of the pharmaceutical composition 200-700 mOsmole/kg. According to the required osmotic pressure, those skilled in the art can determine the content of the osmotic pressure regulator.
  • the pharmaceutically acceptable carrier is a liposome.
  • the liposome can be any liposome capable of encapsulating nucleic acid, and its diameter can be 25-1000 nm, and can include but not limited to cholesterol and its analogs or derivatives.
  • the dosage of the pharmaceutical composition of the present invention can be a conventional dosage in the art, and the dosage can be determined according to various parameters, especially according to the age, weight and gender of the subject. For example, for female, 3-4 month old mice weighing 25-30 g, based on the amount of the nucleic acid in the pharmaceutical composition, the dosage of the pharmaceutical composition can be 0.01-100 mg/kg body weight, preferably 1-10 mg/kg body weight.
  • the present invention also provides a method for inhibiting the expression of complement component 5 gene in a cell, the method comprising: contacting the cell with the nucleic acid, targeted drug delivery system or pharmaceutical composition as described above to inhibit the expression of complement component 5 gene in the cell.
  • the cell is in a subject, e.g., a human subject, e.g., a subject suffering from a complement component 5-associated disease.
  • the cell is located in vitro.
  • the method is for research purposes or for constructing an animal model.
  • contacting the cell with the nucleic acid inhibits expression of C5 by at least 50%, 60%, 70%, 80%, 90%, 95% (e.g., compared to the expression level of C5 before the cell was first contacted with the nucleic acid; e.g., before the first dose of the nucleic acid was administered to the subject).
  • inhibiting expression of C5 reduces the level of C5 protein in a serum sample of the subject by at least 50%, 60%, 70%, 80%, 90%, or 95%, e.g., compared to the expression level of C5 before the cell was first contacted with the nucleic acid.
  • the present invention also provides the use of the nucleic acid as described above, the targeted drug delivery system as described above, or the pharmaceutical composition as described above in any of the following aspects: 1) treating and/or preventing diseases associated with complement component 5; 2) preparing drugs for treating and/or preventing diseases associated with complement component 5.
  • the disease is: (i) a disease associated with enhanced or elevated complement component 5; or (ii) a disease that would benefit from decreased complement component 5 expression.
  • the disease is a disease associated with complement system activation.
  • the disease is selected from one or more of the following diseases: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), asthma, rheumatoid arthritis (RA); antiphospholipid antibody syndrome; lupus nephritis; ischemia-reperfusion injury; typical or infectious hemolytic uremic syndrome (tHUS); dense deposit disease (DDD); neuromyelitis optica (NMO); multifocal motor neuropathy (MMN); multiple sclerosis (MS); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and thrombocytopenia.
  • PNH paroxysmal nocturnal hemoglobinuria
  • aHUS atypical hemolytic uremic syndrome
  • asthma rheumatoid arthritis
  • RA antiphospholipid antibody syndrome
  • lupus nephritis ischemia-reperfusion injury
  • HELLP thrombotic thrombocytopenic purpura
  • spontaneous abortion pauci-immune vasculitis
  • epidermolysis bullosa recurrent abortion
  • preeclampsia traumatic brain injury, myasthenia gravis, cold agglutinin disease, dermatomyositis, bullous pemphigoid, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome, C3 nephropathy, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, allogeneic transplantation, sepsis, coronary artery disease, dermatomyositis, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis sepsis, septic shock, spinal cord injury, glomerulonephritis, Hashimoto's thyroid
  • the subject may be a mammal, including primates (such as humans, non-human primates, such as monkeys and chimpanzees), non-primates (such as cattle, pigs, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats or mice) or birds.
  • the subject is preferably a primate, more preferably a human.
  • Administration can be by a variety of routes, depending on whether local or systemic treatment is required.
  • the mode of administration can be, but is not limited to, intravenous administration, intra-arterial administration, subcutaneous administration, intraperitoneal administration, transdermal administration (such as by implantation of a device) and administration into soft tissue.
  • the dosage can refer to the above, and will not be repeated here.
  • the nucleic acid, the targeted drug delivery system or the pharmaceutical composition is administered to the subject by subcutaneous administration, intravenous administration and/or intramuscular administration.
  • the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. Temperature and time parameters are allowed to be tested with instrument accuracy. Or acceptable deviation caused by operating accuracy.
  • each sense strand and antisense strand was modified, and the modified sequences are shown in Table 2.
  • a/c/g/u 2'-OMe nucleotides
  • Af/Cf/Gf/Uf 2'-F nucleotides
  • s phosphorothioate diester bond.
  • the sense strand and antisense strand in Table 2 were synthesized into the modified double-stranded siRNA in Table 3 by solid phase synthesis.
  • a/c/g/u 2'-OMe nucleotides
  • Af/Cf/Gf/Uf 2'-F nucleotides
  • s phosphorothioate diester bond.
  • RNAiMAX 1.5 ⁇ L/well
  • siRNA small interfering nucleic acids
  • RNA samples 50 ⁇ L of the prepared lysis solution (as recommended by the Cells-to-CT kit (ThermoFisher Scientific, Cat#4391851c)) was added and mixed. After standing for 10 minutes, 2.5 ⁇ L of Stop solution was added to terminate the process for 2 minutes.
  • RT-PCR was performed according to the recommendations of High Capacity cDNA Reverse Transcription Kits (Thermo Fisher, Cat. No. 4368814), and each reaction contained 10 ml of lysed liquid.
  • the hepatocyte-targeting conjugate Tri-GalNAc (its specific structure is shown in the above formula I) was added to the siRNA according to Table 5.
  • SN-68002 used as a comparison was prepared according to the disclosure of US9850488B2.
  • a/c/g/u 2'-OMe nucleotides
  • Af/Cf/Gf/Uf 2'-F nucleotides
  • s phosphorothioate diester bond.
  • the siRNA drugs in Table 5 can significantly reduce the expression level of C5 protein.
  • SN-681263 and SN-681274 drugs are significantly better than other drugs in terms of efficacy.
  • the Tri-galNac used in SN-681263 and SN-681274 in Table 6 is the structure shown in Formula I
  • the Tri-galNac used in SN-68002 is Alnylam Tri-GalNAc (L96).
  • the structure shown in Formula I and L96 are both classified as triantennary N-Acetylgalactosamine. Therefore, based on the above effect data, the advantages of the modified sequence of the present invention can also be confirmed.
  • the effect advantages of the naked sequence and the modified sequence in the present invention do not depend on the selection of the targeting vector.
  • the obtained siRNA drug still has significant effect advantages compared with SN-68002 in in vitro cell tests and in vivo experiments.
  • human C5 transgenic mice were subcutaneously injected with 3 mg/kg of SN-681263 or SN-681274 on day 0, and PBS was used as the control group.
  • the human C5 protein in the blood was tracked and observed. The results are shown in Figure 3.
  • both SN-681263 and SN-681274 can significantly reduce the expression level of C5 protein and have a relatively long-lasting efficacy, among which SN-681274 has a better efficacy.
  • both SN-681263 and SN-681274 can reduce the level of C5 protein in serum in a dose-dependent manner, and SN-681274 can maintain a long-term efficacy for at least 28 days.
  • siRNA of the present invention has obvious effect advantages at the sequence level, and its effect in silencing the C5 gene is significantly better than that of the existing advantageous sequences.

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Abstract

La présente invention se rapporte au domaine technique de la biologie et divulgue un acide nucléique ciblant le composant 5 du complément et son utilisation. L'acide nucléique fourni peut inhiber efficacement l'expression de C5, ce qui permet de traiter et/ou de prévenir des maladies liées à l'activation d'un système de complément.
PCT/CN2024/098563 2023-06-16 2024-06-12 Acide nucléique ciblant le composant 5 du complément et son utilisation Pending WO2024255747A1 (fr)

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