WO2018016884A1 - Composition destinée à diagnostiquer un trouble fonctionnel congénital et son utilisation - Google Patents

Composition destinée à diagnostiquer un trouble fonctionnel congénital et son utilisation Download PDF

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Publication number
WO2018016884A1
WO2018016884A1 PCT/KR2017/007801 KR2017007801W WO2018016884A1 WO 2018016884 A1 WO2018016884 A1 WO 2018016884A1 KR 2017007801 W KR2017007801 W KR 2017007801W WO 2018016884 A1 WO2018016884 A1 WO 2018016884A1
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Prior art keywords
iem
ibcd
deficiency
ras
chr1
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Ceased
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PCT/KR2017/007801
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English (en)
Korean (ko)
Inventor
조은해
장자현
이태헌
전영주
유한욱
김기수
이소영
김영은
이준남
김구환
임채현
김민정
황태주
유기영
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GC Genome Corp
GC Medical Science Corp
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Green Cross Genome Corp
Green Cross Medical Science Corp
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Priority claimed from KR1020160092035A external-priority patent/KR102547253B1/ko
Priority claimed from KR1020160092036A external-priority patent/KR102543645B1/ko
Priority claimed from KR1020160092037A external-priority patent/KR102513462B1/ko
Application filed by Green Cross Genome Corp, Green Cross Medical Science Corp filed Critical Green Cross Genome Corp
Publication of WO2018016884A1 publication Critical patent/WO2018016884A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids

Definitions

  • the present invention relates to a composition for diagnosing congenital dysfunction and its use, and more particularly, to inherited blood coagulation disorders (IBD), inborn error of metabolism (IEM) and hereditary developmental disorders (RASopathies, RAS).
  • the present invention relates to a composition capable of detecting a mutation of a gene related to a congenital dysfunction of a newborn or a fetus selected from the group consisting of) and a use thereof.
  • Neonatal or fetal screening was introduced to reduce complications and mortality by early detection and treatment of hereditary metabolic and rare diseases in newborns or fetuses with no symptoms. It has made significant technological progress over the past decades and has made significant contributions to the early diagnosis and treatment of diseases. Recently, the Centers for Disease Control and Prevention (CDC) has been selected as one of the 10 most important public health outcomes. (Centers for Disease Control and Prevention.Ten great public health achievements--United States, 2001-2010.MMWR Morb Mortal Wkly Rep 2011; 60: 619-23.).
  • Neonatal screening was initiated in 1963 by Robert Guthrie's bacterial inhibition assay-based phenylketonuria group screening, and the prevalence of mental retardation has decreased dramatically since the introduction of the test (Guthrie R and Susi AA Pediatrics 1963; 32: 338-43.).
  • Radioimmunoassays, enzyme colorimetric methods, tandem mass spectrometry, and molecular genetic testing methods have been devised and popularized in early 1990 by using tandem mass spectrometry for neonatal screening (Millington DS, Kodo N, Norwood DL, Roe CR. J Inherit Metab). Dis 1990; 13: 321-4.).
  • NGS Next-Generation Sequencing
  • Blood coagulation is a complex and major process that occurs in response to blood vessel damage. This consists in the formation of a thrombus that stops bleeding and begins the repair of damaged blood vessels; Its walls are covered by fibrin and platelets that contain thrombi. The process begins almost immediately after injury.
  • the clotting process involves two types of components: cellular components called platelets and protein components called coagulation factors. Platelets immediately plug in the damaged area; This is called primary hemostasis. Secondary hemostasis occurs simultaneously: proteins in plasma, referred to as coagulation factors or coagulation factors, react in a complex cascade to form fibrin strands that strengthen platelet plugs.
  • the coagulation cascade of secondary hemostasis is divided into two pathways: the endogenous pathway, also called the contact activation pathway, and the exogenous pathway, also called the tissue factor pathway. Not only are a number of coagulation factors involved, but also cofactors and modulators are involved to keep the process accurate.
  • protein C is an essential factor in the main mechanism of coagulation regulation called the "anticoagulant pathway".
  • the active form of protein C (activating protein C) is a serine protease, which breaks down two factors of the coagulation cascade, namely Va and VIIIa, which are essential for the mass production of thrombin when associated with other cofactors (protein S). do. Destruction of these factors negatively regulates the amount of thrombin formed, which leads to an anticoagulant effect.
  • the protein is known to have in particular pleiotropic biological activity such as: antithrombotic activity (Mizutani et al, Blood 95 (12), 3781-3787. 2000; Bernard et al, N Engl J Med. 8; 344 (10): 699-709.
  • FIX Factor IX
  • FVIIIa activated cofactor
  • Factor X is another essential factor of the coagulation cascade.
  • the activated form of FX (FXa) is the only serine protease capable of activating prothrombin to thrombin in combination with its cofactor (coagulant Va factor).
  • factor X which has long been considered as a passive bystander, is a direct entry into a wide variety of cell types through the activation of its two major receptors, protease-activated receptor-1 (PAR-1) and PAR-2. Appears as Recent findings suggest that PAR-2 plays an important role in coordinating the interface between coagulation and disease progression, and plays an important role in point X factor and in fibrotic diseases such as fibrosis, tissue remodeling and cancer. (Borensztajn et al., Am J Pathol. 172 (2): 309-20, 2008).
  • hemophilia A is the most common hereditary blood clotting disease in the world, with the exception of von Willebrand disease, which accounts for 80-85% of all hemophilia and the incidence of survival is 1 in 5,000-10,000 boys. Is reported. Hemophilia B is more rare and is estimated to be about 1/5 of hemophilia A.
  • hemophilia A and B have decreased activity in blood tests.
  • the activity of factors VIII and IX is about 50-150%, and hemophilia A and B have decreased activity in blood tests.
  • the coagulation factor again severe (factor VIII or factor IX activity 1% or less), moderate (factor activity 1-5%), mild (factor activity 5-30%), steady (factor activity 30-50%) )
  • the symptoms vary depending on the severity.
  • severe hemophilia A spontaneous bleeding can occur at any time without special trauma.
  • concentration VIII concentrate concentration of hemophilia A is about 70%, 15%, 15% for severe, moderate and mild patients, and hemophilia B is about 50%, 30% and 20%, respectively.
  • the frequency of bleeding is generally known once a week for severe patients, once a month for moderate patients, and once a year for mild patients. Joints and muscles are the most common bleeding sites. Joint bleeding is especially pronounced between the ages of 15 and 25, and repeated bleeding suffers from the construction of joints due to hemophilic arthropathy for an average of 50 years.
  • the Medical and Scientific Advisory Council of the National Hemophilia Foundation, the World Hemophilia Federation, and the World Health Organization are all the best ways to prevent bleeding and chronic arthrosis. Retention therapy is recommended for over 46 weeks.
  • the standard guideline for the most commonly proposed maintenance regimen at present is the injection of a coagulation factor agent of 25-40 IU / kg three times a week for hemophilia A patients and twice a week for hemophilia B patients.
  • Hereditary metabolic diseases are caused by a lack of enzymes or coenzymes that are responsible for the biochemical metabolic pathways in our bodies. Deficiency symptoms occur due to the inability to produce the final necessary substance, and unnecessary precursors accumulate in various important organs (brain, heart, liver, kidneys, etc.) and cause excess symptoms such as intellectual disability. Symptoms and treatments vary by disease, depending on which metabolic pathway is defective. Each disease is rare, but the range of genetic metabolic diseases is very diverse, there are more than 500 species, due to the development of genetic and biochemical diagnostic methods, the disease is newly added.
  • hereditary metabolic disease is an abnormality of the gene that makes the enzyme, the deficiency of the enzyme or coenzyme that is responsible for the biochemical metabolic pathways of our body, and as a result, various metabolic disorders are known to occur.
  • various genetic methods are used, with autosomal recessive inheritance being the most common.
  • Genetic metabolic disorders have many symptoms that occur during neonatal period. Two to three days after lactation, nonspecific symptoms such as vomiting, sagging, convulsions, and lethargy appear, similar to sepsis due to neonatal infection. Galactosemia, organic aciduria, urea cycle metabolic diseases, maple diabetes mellitus, tyrosinemia and the like. If the enzyme remains active, it may be diagnosed during infancy. Symptoms such as intellectual disability, developmental regression, acute illness, vomiting, and loss of consciousness may be diagnosed later.
  • Phenylketonuria PKU
  • Maple Syrup Urine Disease MSUD
  • Homocystinuria Citrullinemia type I
  • Argininosuccinic Aciduria Argininosuccinic Aciduria
  • Tyrosinemia Type I Isovaleric Acidemia
  • Glutaric Acidemia Type I 3-hydroxy-3-methylglycol 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
  • Multiple Carboxylase Deficiency Vitamin 12 Methylmalonic Acidemia, Vitamin B-12 Non-responsive
  • Propionic Acidemia Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
  • Long-chain Acyl-CoA Dehydrogenase Deficiency Long-chain Acyl-CoA Dehydrogenase Deficiency (Long-chain 3-Hydroxyacyl-CoA Dehydrogenase) (LCAHD) Deficiency
  • the general principles of treatment for hereditary metabolic disorders include: a diet that limits the substrate of the deficient enzyme to remove toxic precursors accumulated by blocking the metabolic pathways and prevent further precursors (depending on the disease). Since prescriptions for restricted diets are different, a specialist's prescription and consultation with a professional dietitian are required. Metabolic pathways are not produced because they are blocked, but coenzymes or enzymes may be administered directly to supplement the final material needed by the body. Some diseases are transplanted with necessary organs (liver, kidney, bone marrow, etc.) according to indications, and research is being conducted on gene therapy.
  • Hereditary developmental disorder is a rare disease in newborns or fetuses caused by mutations in genes encoding proteins involved in the Rat Sarcoma / Mitogen-Activated Protein Kinase (RASP) signaling pathway in embryos.
  • Noonan syndrome Noonan syndrome-like disorder, Costello syndrome, Cardiofaciocutaneous syndrome, Neurofibromatosis (type 1), Legus syndrome (Legius syndrome) and LEOPARD syndrome.
  • the present inventors have a high sensitivity and accuracy for the diagnosis of rare or fetal rare disease, especially Inherited Bleeding Coagulation Disorders (IBD), Inborn Error of Metabolism (IEM) or Hereditary Developmental Disorders (RASopathies, RAS) Efforts have been made to develop the composition, in which genes containing mutations occurring in neonatal or fetal rare diseases are fragmented based on specific criteria, and analysis of neonatal or fetal derived samples using compositions comprising complementary probes for each fragment. In addition, it was confirmed that the variation information of the sample can be detected with high sensitivity and accuracy, and completed the present invention.
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RASopathies Hereditary Developmental Disorders
  • Another object of the present invention is to provide a genetic mutation detection method for detecting a congenital dysfunction of a newborn or fetus using the diagnostic composition.
  • the present invention also comprises the steps of: (a) capturing a target gene using the composition in a biological sample; (b) determining the sequence of the captured gene; And (c) detecting the genetic variation by analyzing the determined base sequence; Inherited Bleeding Coagulation Disorders (IBD), Inborn Error of Metabolism (IEM), and hereditary developmental disorders (RASopathies).
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RASopathies hereditary developmental disorders
  • the invention also relates to a congenital function of a newborn or fetus selected from the group consisting of Inherited Bleeding Coagulation Disorders (IBCD), Inborn Error of Metabolism (IEM), and Hereditary Developmental Disorders (RASopathies, RAS).
  • IBCD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RASopathies Hereditary Developmental Disorders
  • the present invention also relates to a newborn or fetus from a group consisting of Inherited Bleeding Coagulation Disorders (IBD), Inborn Error of Metabolism (IEM) and Hereditary Developmental Disorders (RASopathies, RAS) using the composition.
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RAS Hereditary Developmental Disorders
  • FIG. 1 is a diagram illustrating a method for detecting genetic variation in a sample using a composition for diagnosing congenital dysfunction of a newborn or fetus according to the present invention.
  • NGS Next Generation Sequencing
  • next generation sequencing and next generation sequencing This refers to a technique for fragmenting the whole genome and sequencing the fragment at a large capacity based on chemical hybridization, and includes technologies from Agilent, Illumina, Roche, and Life Technologies, and has a broad meaning.
  • the furnace is defined as including a technology of Pacificbio, a third generation technology, a technology such as Nanopore Technology, and a fourth generation technology.
  • SNV Single Nucleotide Variation
  • insertion / deletion mutation means an insertion or deletion variation that can change the number of nucleic acids in a gene.
  • mutations of genes associated with congenital dysfunction such as Inherited Bleeding Coagulation Disorders (IBD), Inborn Error of Metabolism (IEM), and hereditary developmental disorders (RASopathies, RAS) are highly sensitive and highly sensitive. When detecting with accuracy, we tried to confirm that it can be diagnosed accurately.
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RASopathies hereditary developmental disorders
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RAS hereditary developmental disorders
  • the present invention F5, F13B, MCFD2, FGB, FGA, FGG, F11, F13A1, SERPINE1, F2, VWF, F7, F10, SERPINF2, LMAN1, F9, F8, HMGCL, ACADM, DBT, HADHA , HADHB, PCCB, MMAA, SLC22A5, MUT, BCKDHB, ASL, ASS1, ACAT1, PAH, MMAB, PCCA, IVD, FAH, ACADVL, GCDH, BCKDHA, HLCS, CBS, NRAS, RIT1, SOS1, RAF1, BRAF, SHOC2 Inherited Bleeding Coagulation Disorders (IBC), including polynucleotides capable of detecting mutations in one or more genes consisting of HRAS, CBL, KRAS, PTPN11, SPRED1, MAP2K1, NF1, and MAP2K2 It relates to a composition for diagnosing congenital dysfunction
  • the invention also relates to a congenital function of a newborn or fetus selected from the group consisting of Inherited Bleeding Coagulation Disorders (IBCD), Inborn Error of Metabolism (IEM), and Hereditary Developmental Disorders (RASopathies, RAS). It relates to the use of the composition for the diagnosis of disorders.
  • IBCD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RASopathies Hereditary Developmental Disorders
  • the present invention also relates to a newborn or fetus from a group consisting of Inherited Bleeding Coagulation Disorders (IBD), Inborn Error of Metabolism (IEM) and Hereditary Developmental Disorders (RASopathies, RAS) using the composition.
  • IBD Inherited Bleeding Coagulation Disorders
  • IEM Inborn Error of Metabolism
  • RAS Hereditary Developmental Disorders
  • the polynucleotide may be a probe containing a sequence complementary to the exon region or a primer capable of amplifying the sequence, but is not limited thereto.
  • the “gene exon region” of the present invention includes an intron sequence of ⁇ 100 bp, specifically ⁇ 50 bp, more specifically ⁇ 20 bp in the exon region and exon region translated into protein.
  • probe refers to an oligonucleotide specific for a single strand having a base sequence that is sufficiently complementary to the target base sequence to be detected to hybridize.
  • 'Oligonucleotide' of the present invention generally refers to a nucleotide polymer consisting of about 10 to about 100 nucleotides. However, the length of the nucleotides may be 100 or more or 10 or less.
  • the 'nucleotide' of the present invention is the basic unit of nucleic acid consisting of phosphate groups, 5-carbosaccharides and nitrogen bases.
  • 5-Tanose in RNA is ribose.
  • the 5-saccharide in DNA is 2-deoxyribose.
  • the sugars contain hydroxyl groups (-OH) in 5-saccharide-2.
  • the term also includes analogs of these basic units, such as methoxy groups at the 2 position of ribose.
  • 'hybridization' of the present invention is meant the annealing of the complementary sequence to the target nucleic acid (the sequence to be detected).
  • the ability of two nucleic acid polymers, including complementary sequences, to find each other and hybridize through base pair interactions is a well known phenomenon.
  • a 'hybrid' of the present invention is a complex formed between two single-stranded nucleotide sequences by Watson-Crick base pair or non-standard base pair between complementary bases.
  • the 'label' of the present invention refers to any atom or molecule capable of providing a detectable (specifically quantifiable) signal and binding to a nucleic acid.
  • the label can provide a detectable signal by fluorescence, radioactivity, chromaticity, X-ray diffraction or absorption, magnetism, or the like.
  • the 'specificity' of the present invention refers to the characteristics of the probe to describe the ability to distinguish between target and nontarget sequences.
  • the specificity of a probe means that the nucleotide sequence hybridizes with a given target sequence and is substantially free of hybridization with the nontarget sequence or with minimal hybridization with the nontarget sequence. Probe specificity depends on sequence and assay conditions.
  • the polynucleotide of the present invention can be cloned using a conventional cloning method (Maniatis, T., et al. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York, 1982) or using a commercially available DNA synthesizer. Chemically synthesized to obtain a large amount.
  • the probes of the present invention may be specific for any conventional label, e.g., radioisotopes such as 32P, 35S, 125I, 3H, and 14C, residues with immune properties (e.g., antigens or haptens), and specific reagents for some reagents.
  • residues that provide a detectable enzymatic reaction e.g., enzymes, coenzymes, enzyme substrates or substrates participating in the enzyme reaction
  • residues that provide a detectable enzymatic reaction e.g., enzymes, coenzymes, enzyme substrates or substrates participating in the enzyme reaction
  • a non-radioactive material containing a residue and the like.
  • the gene list used in one embodiment of the present invention is shown in Table 1 below.
  • the polynucleotide may be characterized in that it can detect exon mutations of each gene, maintain a GC ratio in the range of 40 to 60%, and complementary to the gene sequence without the repeat sequence.
  • gene fragments satisfying the above conditions were constructed as shown in Table 2 below.
  • the mutation of the gene may be characterized in that it occurs at one or more positions selected from the group consisting of the exon region described in Table 2.
  • the polynucleotide may be characterized by complementary to part or all of one or more gene sequences selected from the group consisting of SEQ ID NOs: 1 to 751.

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Abstract

La présente invention concerne une composition destinée à diagnostiquer des troubles fonctionnels congénitaux et, plus particulièrement, une composition destinée à diagnostiquer des troubles fonctionnels congénitaux, dans laquelle un polynucléotide contenant une séquence qui est complémentaire d'une séquence dans une région d'exon d'un gène particulier est choisi dans le groupe constitué par les troubles héréditaires de la coagulation/saignement (IBCD), une erreur inné du métabolisme (IEM), et des RASopathies (RAS) ; et une utilisation de cette composition. La composition selon la présente invention est utile en ce que des mutations géniques liées à des troubles fonctionnels congénitaux chez les nourrissons ou les fœtus peuvent être détectées avec une sensibilité et une précision élevées lorsque la composition est utilisée.
PCT/KR2017/007801 2016-07-20 2017-07-20 Composition destinée à diagnostiquer un trouble fonctionnel congénital et son utilisation Ceased WO2018016884A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR10-2016-0092036 2016-07-20
KR1020160092035A KR102547253B1 (ko) 2016-07-20 2016-07-20 유전성 대사질환 진단용 조성물 및 이의 용도
KR10-2016-0092037 2016-07-20
KR1020160092036A KR102543645B1 (ko) 2016-07-20 2016-07-20 유전성 발달장애 진단용 조성물 및 이의 용도
KR10-2016-0092035 2016-07-20
KR1020160092037A KR102513462B1 (ko) 2016-07-20 2016-07-20 유전성 혈액응고 장애 진단용 조성물 및 이의 용도

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CN111440856A (zh) * 2018-12-28 2020-07-24 北京迈基诺基因科技股份有限公司 一种用于检测甲基丙二酸血症相关致病基因的探针组及试剂盒
CN114008209A (zh) * 2019-04-12 2022-02-01 马萨诸塞大学 Aav介导的枫糖尿症(msud)基因疗法
CN114410766A (zh) * 2021-11-24 2022-04-29 广州知力医学诊断技术有限公司 一种血栓与出凝血性疾病检测panel及其应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440856A (zh) * 2018-12-28 2020-07-24 北京迈基诺基因科技股份有限公司 一种用于检测甲基丙二酸血症相关致病基因的探针组及试剂盒
CN111440856B (zh) * 2018-12-28 2022-10-21 北京迈基诺基因科技股份有限公司 一种用于检测甲基丙二酸血症相关致病基因的探针组及试剂盒
CN114008209A (zh) * 2019-04-12 2022-02-01 马萨诸塞大学 Aav介导的枫糖尿症(msud)基因疗法
US12398378B2 (en) 2019-04-12 2025-08-26 University Of Massachusetts AAV-mediated gene therapy for maple syrup urine disease (MSUD)
CN114410766A (zh) * 2021-11-24 2022-04-29 广州知力医学诊断技术有限公司 一种血栓与出凝血性疾病检测panel及其应用

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