WO2019242751A1 - Petits biomarqueurs moléculaires pour la néphropathie et leurs applications - Google Patents

Petits biomarqueurs moléculaires pour la néphropathie et leurs applications Download PDF

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Publication number
WO2019242751A1
WO2019242751A1 PCT/CN2019/092332 CN2019092332W WO2019242751A1 WO 2019242751 A1 WO2019242751 A1 WO 2019242751A1 CN 2019092332 W CN2019092332 W CN 2019092332W WO 2019242751 A1 WO2019242751 A1 WO 2019242751A1
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Prior art keywords
nephropathy
biomarker
level
biological sample
detection level
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PCT/CN2019/092332
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English (en)
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Chao-Jung Chen
Fuu-Jen Tsai
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China Medical University
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Publication of WO2019242751A1 publication Critical patent/WO2019242751A1/fr

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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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7057—(Intracellular) signaling and trafficking pathways
    • G01N2800/7066—Metabolic pathways
    • G01N2800/7076—Amino acid metabolism

Definitions

  • the present invention relates to a biomarker, method and assay kit for identifying and screening nephropathy and monitoring progression of nephropathy.
  • nephropathy patients a decreased level of certain metabolites including N1-methylguanosine, 7-methyluric acid, xanthosine and histidine, or an increase level of the amino acid, valine, can be detected in the urine of a subject with nephropathy, including one at the early stage of nephropathy, when compared to a normal level in a control (healthy) subject free of nephropathy.
  • the metabolites including N1-methylguanosine, 7-methyluric acid, xanthosine and histidine, and the amino acid, valine, can be used as a specific biomarker for diagnosing nephropathy, especially for early diagnosis, and also be used to monitor progression of nephropathy in patients with nephropathy.
  • the present invention provides a method for detecting nephropathy in a subject, the method comprising:
  • the CKD is early CKD, particularly stage 1 or stage 2, or the CKD is stage 3 or stage 4 CKD.
  • the articles “a” and “an” refer to one or more than one (i.e., at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the term “about” or “approximately” refers to a degree of acceptable deviation that will be understood by persons of ordinary skill in the art, which may vary to some extent depending on the context in which it is used. In general, “about” or “approximately” may mean a numeric value having a range of ⁇ 10%around the cited value.
  • the term “comprise” or “comprising” is generally used in the sense of include/including which means permitting the presence of one or more features, ingredients or components.
  • the term “comprise” or “comprising” encompasses the term “consists” or “consisting of. ”
  • the terms “subject, ” “individual” and “patient” refer to any mammalian subject for whom diagnosis, prognosis, treatment, or therapy is desired, particularly humans. Other subjects may include cattle, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and so on.
  • the term "physiological parameter" refers generally to any parameter that may be monitored to determine one or more quantitative physiological levels and/or activities associated with the patient.
  • the physiological parameter include but are not limited to age, gender, systolic blood pressure (SBP) , diastolic blood pressure (DBP) , fasting blood glucose (FBG) , hemoglobin A1c (HbA1c) , diabetes duration, creatinine, estimated glomerular filtration rate (eGFR) , albuminuria, urine albumin to creatinine ratio (ACR) , and any combination thereof.
  • the physiological parameter includes fasting blood glucose (FBG) and/or diastolic blood pressure (DBP) .
  • Table A different stages of CKD.
  • diabetes refers to renal diseases resulting from diabetes.
  • the diabetes is type 2 diabetes.
  • the present disclosure is based (at least in part) on the identification of one or more novel reliable nephropathy biomarker, i.e. the metabolites including N1-methylguanosine, 7-methyluric acid, xanthosine and histidine, and the amino acid, valine.
  • a decreased level of certain metabolites including N1-methylguanosine, 7-methyluric acid, xanthosine and histidine, or an increase level of the amino acid, valine is found in the urine samples of individuals suffering from nephropathy.
  • the nephropathy detection method described herein can identify whether an individual has, is suspected of having, or is at the risk of developing nephropathy.
  • the detection methods described herein can be applied to any subject, especially as an initial, regular and routine screening method to identify those with nephropathy or at the risk for progressing nephropathy.
  • a biomarker for nephropathy as described herein is as follows:
  • the method for screening nephropathy patients and monitoring nephropathy progression described herein can use these molecules as a reliable biomarker to perform.
  • the detection method described herein can be used as an early-stage screening method for any individual to detect whether it is likely to have nephropathy (especially early nephropathy) .
  • N1-methylguanosine, 7-methyluric acid, xanthosine, and histidine is observed to be decreasing over time (e.g., the amount of N1-methylguanosine, 7-methyluric acid, xanthosine, and histidine in the later obtained sample is lower than that in the sample obtained earlier) , the individual is diagnosed as having, being suspected of having, or at risk of having nephropathy. If the individual is a nephropathy patient, then decreasing trend of the amount of N1-methylguanosine, 7-methyluric acid, xanthosine, and histidine indicates progression (deterioration) of nephropathy.
  • valine if the trend of an amino acid biomarker, valine, is observed to be increasing over time (e.g., the amount of valine in the later obtained sample is higher than that in the sample obtained earlier) , the individual is diagnosed as having, being suspected of having, or at risk of having nephropathy. If the individual is a nephropathy patient, then increasing trend of the amount of valine indicates progression (deterioration) of nephropathy.
  • the precursor ion/fragment ion (collision energy) values of valine, 7-methyluric acid, N1-methylguanosine, and xanthosine were 118.07/72.08 (10 eV) , 181.03/123.00 (30 eV) , 296.06/164.05 (20 eV) and 283.07/151.03 (20 eV) , respectively.
  • Figs. 2A-2B show six volcano plots of different groups, which were constructed by plotting the log of the P-value on the y-axis (base 10) and the log of the value of fold change between the two conditions. When the log of the fold change is used, the changes in both directions (up and down) appear equidistant from the center. There were 85/232 (#of positive ions/negative ions) , 30/95, and 44/98 peak candidates found in the healthy vs. macro, healthy vs. T2DM, and T2DM vs. T2DM+micro comparisons, respectively.
  • Healthy VS macro The median of Xanthosine is 0.8024; The median of N1-methylguanosine is 0.6778; The median of 7-Methyluric acid is 1.0107; The median of Aspartate is 2.0788.
  • T2DM VS T2DM+micro The median of Xanthosine is 1.0102; The median of N1-methylguanosine is 0.7360; The median of 7-Methyluric acid is 0.7993; The median of Aspartate is 3.2213.
  • N1-methylguanosine Median + and 7-Methyluric acid ⁇ Median
  • Methyluric acid formation from methylxanthine is catalyzed by xanthine oxidase and there are four methyluric acid isoforms: 1-, 3-, 7-, and 9-methyluric acid.
  • 7-methyluric acid concentration in urine is significantly lower in macro than in healthy individuals.
  • the decreased content of 7-methyuric acid in urine of macro patients may be also due to its reduced renal clearance.
  • a panel of amino acid markers in urine may be used to evaluate the risk of DM development. Due to their high AUC values that differentiated T2DM+micro subjects from T2DM subjects, N1-methylguanosine and xanthosine could be used as markers that predict the development of nephropathy in T2DM patients.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un biomarqueur, un procédé et un kit de dosage pour identifier et cribler une néphropathie et surveiller un traitement de la néphropathie.
PCT/CN2019/092332 2018-06-21 2019-06-21 Petits biomarqueurs moléculaires pour la néphropathie et leurs applications WO2019242751A1 (fr)

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US62/688,147 2018-06-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150736A3 (fr) * 2022-02-04 2023-10-12 Board Of Regents, The University Of Texas System Procédés et compositions associés à l'évaluation et au traitement d'une maladie rénale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013188333A1 (fr) * 2012-06-13 2013-12-19 Metabolon, Inc. Biomarqueurs associés à la néphrotoxicité et leurs méthodes d'utilisation

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CN102859357A (zh) * 2010-04-27 2013-01-02 希森美康株式会社 肾脏病诊断用标志物及其利用
SG11201710246YA (en) * 2015-06-10 2018-01-30 Univ Kanazawa Disease-state biomarker for renal disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013188333A1 (fr) * 2012-06-13 2013-12-19 Metabolon, Inc. Biomarqueurs associés à la néphrotoxicité et leurs méthodes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KURT BJ ET AL.: "Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity", TOXICOLOGIC PATHOLOGY, vol. 37, no. 3, 20 April 2009 (2009-04-20), pages 280 - 292, XP008111286, DOI: 10.1177/0192623309332992 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150736A3 (fr) * 2022-02-04 2023-10-12 Board Of Regents, The University Of Texas System Procédés et compositions associés à l'évaluation et au traitement d'une maladie rénale

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