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WO2021150011A1 - Biomarqueur pour le diagnostic précoce du diabète ou des complications diabétiques, et utilisation associée - Google Patents

Biomarqueur pour le diagnostic précoce du diabète ou des complications diabétiques, et utilisation associée Download PDF

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Publication number
WO2021150011A1
WO2021150011A1 PCT/KR2021/000784 KR2021000784W WO2021150011A1 WO 2021150011 A1 WO2021150011 A1 WO 2021150011A1 KR 2021000784 W KR2021000784 W KR 2021000784W WO 2021150011 A1 WO2021150011 A1 WO 2021150011A1
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WIPO (PCT)
Prior art keywords
diabetic
diabetes
adam2
diabetic complications
protein
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Ceased
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PCT/KR2021/000784
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English (en)
Korean (ko)
Inventor
조호찬
배윤위
박재형
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Industry Academic Cooperation Foundation of Keimyung University
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Industry Academic Cooperation Foundation of Keimyung University
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Publication of WO2021150011A1 publication Critical patent/WO2021150011A1/fr
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Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Diabetes mellitus ( ⁇ ; diabetes mellitus) is a metabolic disease characterized by hyperglycemia caused by defects in insulin secretion or insulin action. It is a chronic degenerative disease accompanied by
  • non-insulin-dependent type 2 diabetes patients account for 90-95% of all diabetes patients, and as people in developed countries as well as developing countries gradually decrease physical activity and increase obesity, the occurrence of type 2 diabetes This is increasing at a frightening rate.
  • the existing diabetes diagnosis only the blood glucose level or the glycated hemoglobin level is diagnosed, but since this is a clinical sign after the progress of diabetes is sufficiently advanced, it is difficult to use as a tool for early diagnosis. can't see that
  • Diabetic complications that cause secondary diseases due to diabetes include diabetic retinopathy and diabetic nephropathy.
  • diabetic retinopathy In particular, according to the Health Insurance Review and Assessment Service, about 200 diabetic patients in 2012 The number of diabetic retinopathy patients increased from about 260,000 in 2012 to about 2.45 million in 2016, an increase of 21% from 10,000 to about 2.45 million in 2016. .
  • An object of the present invention is to provide a biomarker for early diagnosis of diabetes or diagnosis of diabetic complications.
  • Another object of the present invention is to provide a composition or diagnostic kit for early diagnosis of diabetes or diabetic complications using the biomarker.
  • the present invention provides a biomarker for early diagnosis of diabetes or diabetic complications including ADAM2 (ADAM Metallopeptidase Domain 2).
  • ADAM2 ADAM Metallopeptidase Domain 2
  • the diabetic complication may be diabetic retinopathy or diabetic nephropathy.
  • the present invention provides a composition for early diagnosis of diabetes or diabetic complications comprising an agent for measuring the mRNA or protein level of ADAM2.
  • the diabetic complication may be diabetic retinopathy or diabetic nephropathy.
  • the agent for measuring the mRNA level of ADAM2 may be a primer pair, a probe, or an antisense nucleotide that specifically binds to the gene of the marker.
  • the agent for measuring the protein level of ADAM2 is an antibody that specifically binds to the protein or peptide fragment, an interacting protein, a ligand, nanoparticles or an aptamer ( aptamer) may be included.
  • the measurement of the protein expression level is performed using an antibody that specifically binds to a protein or peptide fragment, an interacting protein, a ligand, nanoparticles or an aptamer. can do.
  • the information providing method for early diagnosis of diabetes further comprises the step of determining the early stage of diabetes when the gene expression level or protein expression level of ADAM2 decreases compared to a normal subject.
  • the information providing method for diagnosing diabetic complications comprises the steps of determining the diabetic complication stage when the gene expression level or protein expression level of ADAM2 increases compared to a normal subject or a diabetic subject may further include.
  • step (b) may be performed by a statistical analysis method.
  • the term “diagnostic biomarker” refers to a significant increase or decrease in gene expression level or protein expression level in an individual with pre-diabetes or diabetic complications compared to a normal control group (individuals that are not diabetic or diabetic complications).
  • a normal control group individuals that are not diabetic or diabetic complications.
  • Contains organic biomolecules such as polypeptides or nucleic acids (eg, mRNA, etc.), lipids, glycolipids, glycoproteins, sugars (monosaccharides, disaccharides, oligosaccharides, etc.), etc., preferably ADAM2 (ADAM Metallopeptidase Domain 2) .
  • the results of performing the antibody array on the blood of normal people, pre-diabetes and diabetic patients were visualized as clusters and heat maps ( FIG. 1 ).
  • ADAM2 ADAM Metallopeptidase Domain 2 biomarkers were selected, and in the case of ADAM2, the expression of ADAM2 was significantly reduced compared to normal in the pre-diabetes stage (FIGS. A pattern ( FIG. 6 ) in which the expression significantly increased in diabetic retinopathy and diabetic nephropathy was confirmed.
  • ADAM2 expression decreased 4 to 5 times in the early stage of diabetes (pre-diabetes) compared to normal subjects.
  • ELISA quantitative analysis
  • ADAM2 expression was increased 11 to 12 times compared to normal people and 7 to 8 times compared to diabetic patients.
  • ADAM2 expression increased 3 to 4 times compared to normal people and 2 to 2.5 times compared to diabetic patients.
  • the diabetic complications are characterized in that diabetic retinopathy or diabetic nephropathy.
  • the agent for measuring the mRNA level of ADAM2 is characterized in that it is a primer pair, probe, or antisense nucleotide that specifically binds to the ADAM2 gene.
  • Primer pairs, probes or antisense nucleotides can be designed.
  • the term "measurement of protein expression level” is a process of confirming the presence and expression level of a protein expressed from a biomarker for early diagnosis of diabetes or diagnosis of diabetic complications in a biological sample.
  • the amount of the protein can be confirmed using an antibody, an interacting protein, a ligand, nanoparticles, or an aptamer that specifically binds to a protein or peptide fragment of the gene.
  • an antibody refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction.
  • an antibody refers to an antibody that specifically binds to a biomarker of the present invention.
  • Antibodies of the present invention include polyclonal antibodies, monoclonal antibodies and recombinant antibodies.
  • the present invention relates to a kit for diagnosing early diabetes or diabetic complications comprising the composition for diagnosing early diabetes or diabetic complications.
  • the information providing method for diagnosing diabetic complications may further include determining the diabetic complication stage when the gene expression level or protein expression level of ADAM2 increases compared to a normal subject or a diabetic subject.
  • the analysis in step (b) may be analyzed using a statistical method or algorithm to improve the accuracy of diagnosis, and a linear or non-linear regression analysis method, a preceding or non-linear classification analysis method, a logistic regression analysis method (logistic regression analysis method) regression), Analysis of Variance (ANOVA), neural network analysis method, genetic analysis method, support vector machine analysis method, hierarchical analysis or clustering analysis method, hierarchical algorithm or kernel principal component analysis using decision tree method, Markov Blanket analysis method, recursive feature elimination or entropy-based regression feature elimination analysis method, forward floating search or backward floating search analysis method, and their methods
  • An analysis method selected from the group consisting of combinations may be used.
  • the statistical method uses a logistic regression analysis method, but is not limited thereto.
  • ADAM2 biomarker for early diagnosis of diabetes or diabetic complications of the present invention was specifically confirmed to be reduced in expression compared to normal subjects in the pre-diabetes stage, and diabetic retinopathy and diabetic complications, which are diabetic retinopathy and diabetes mellitus.
  • diabetic retinopathy and diabetic complications which are diabetic retinopathy and diabetes mellitus.
  • nephropathy diabetic nephropathy
  • HV normal people
  • Pre-DM pre-diabetes
  • T2DM diabetic patients
  • HV normal
  • Pre-DM pre-diabetic
  • T2DM diabetic patients
  • HV normal
  • Pre-DM pre-diabetic
  • T2DM diabetic patients
  • 5 is data visualized as clusters and heatmaps of the results of performing the antibody array on blood of normal people, diabetic patients, and diabetic nephropathy patients (Nephro).
  • the z-score of ab with 1.5fc and p ⁇ 0.05 under at least one of the comparative conditions is shown.
  • FIG. 6 is data comparing ADAM2 expression levels in diabetic retinopathy (a) and diabetic nephropathy (b) with normal subjects and pre-diabetic patients.
  • T2DM means a patient diagnosed with diabetes.
  • T2DM Retinopathy refers to a patient diagnosed with diabetic retinopathy
  • T2DM Nephropathy refers to a patient diagnosed with diabetic nephropathy.
  • the concentration of the purified sample was measured using a BCA protein analysis kit (Pierce, USA) and a nanophotometer (NanoPhotometerTM, Implen, UK), and the purity of the purified sample was confirmed by UV spectrum.
  • An antibody microarray slide (Fullmoon biosystems, Canada) was placed on a Petri dish and treated with 30 ml of blocking solution, then incubated on a shaker at 60 rpm for 30 minutes at room temperature and washed with distilled water. , this was repeated 3 times. After blocking the slides were washed with Milli-Q grade water.
  • Slide scans were performed using a GenePix 4100A scanner (Axon Instrument, USA). Slides were completely dried prior to scanning and scanned within 24-48 hours. Slides were scanned with 10 ⁇ m resolution, optimal laser power and PMT. After the scan images were obtained, they were gridded and quantified with GenePix 7.0 software (Axon Instrument, USA).

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Microbiology (AREA)
  • Organic Chemistry (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Cell Biology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un biomarqueur pour le diagnostic précoce du diabète ou des complications diabétiques, ainsi que son utilisation et, plus particulièrement, un biomarqueur ADAM2 pour le diagnostic précoce du diabète ou des complications diabétiques, une composition pour le diagnostic précoce du diabète ou des complications diabétiques au moyen dudit biomarqueur, un kit de diagnostic, ainsi qu'une méthode destinée à fournir des informations nécessaires au diagnostic précoce du diabète ou des complications diabétiques. Il a été établi que le biomarqueur ADAM2 pour le diagnostic précoce du diabète ou des complications diabétiques selon l'invention présentait un niveau d'expression particulièrement réduit au stade prédiabétique, par rapport à des individus sains. En outre, un schéma a été établi, dans lequel l'expression dudit marqueur était encore accrue en cas de rétinopathie et de néphropathie diabétiques, qui sont des complications diabétiques, par rapport à des individus sains ou diabétiques. Le biomarqueur selon l'invention peut par conséquent être utile dans le diagnostic précoce du diabète ou des complications diabétiques.
PCT/KR2021/000784 2020-01-22 2021-01-20 Biomarqueur pour le diagnostic précoce du diabète ou des complications diabétiques, et utilisation associée Ceased WO2021150011A1 (fr)

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KR20200008809 2020-01-22
KR10-2020-0008809 2020-01-22

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Cited By (1)

* Cited by examiner, † Cited by third party
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WO2023072261A1 (fr) * 2021-10-29 2023-05-04 上海市第一人民医院 Marqueur lipidique sérique associé aux exsudats durs du fond de l'oeil dans la rétinopathie diabétique, et son application

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KR102525144B1 (ko) * 2021-03-04 2023-04-21 계명대학교 산학협력단 당뇨 전단계 진단 또는 당뇨 합병증 발병 예측용 바이오마커 및 이의 용도
KR102693478B1 (ko) * 2022-03-14 2024-08-07 계명대학교 산학협력단 당뇨 전단계 및 당뇨병 진단용 바이오마커 및 이의 용도

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072261A1 (fr) * 2021-10-29 2023-05-04 上海市第一人民医院 Marqueur lipidique sérique associé aux exsudats durs du fond de l'oeil dans la rétinopathie diabétique, et son application

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