WO2023214599A1 - Composition pour le diagnostic de la maladie de charcot-marie-tooth et procédé de fourniture d'informations pour le diagnostic de celle-ci - Google Patents

Composition pour le diagnostic de la maladie de charcot-marie-tooth et procédé de fourniture d'informations pour le diagnostic de celle-ci Download PDF

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WO2023214599A1
WO2023214599A1 PCT/KR2022/006439 KR2022006439W WO2023214599A1 WO 2023214599 A1 WO2023214599 A1 WO 2023214599A1 KR 2022006439 W KR2022006439 W KR 2022006439W WO 2023214599 A1 WO2023214599 A1 WO 2023214599A1
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marie
charcot
tooth disease
plasma
serum
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Korean (ko)
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박환태
조영래
김영희
윤별아
김종국
최병옥
남수현
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동아대학교 산학협력단
사회복지법인 삼성생명공익재단
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    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a composition for diagnosing Charcot-Marie-Tooth disease and a method for providing information for diagnosis.
  • Charcot-Marie-Tooth disease is a disease that causes progressive sensory impairment and muscle weakness, and is also called hereditary motor and sensory neuropathy.
  • Charcot-Marie-Tooth disease is mainly characterized by muscle weakness and atrophy that gradually progresses from the distal to the proximal lower extremities, including areflexia, distal sensory loss, pes cavus, and hearing loss. Deafness may also appear. The onset usually occurs around the teenage years, but rarely occurs after the age of 30.
  • There are currently over 120 known causative genes for Charcot-Marie-Tooth disease and although symptoms are caused by mutations in the same gene, the clinical phenotype and age of onset are very diverse, making diagnosis difficult in the absence of a family history. Nerve biopsy can be helpful in diagnosis, but it is an invasive test and is not easy to use for diagnosis.
  • next generation sequencing has been actively used in the diagnosis of diseases, and research is being conducted very actively to isolate causative genes and identify molecular biological mechanisms.
  • NGS next generation sequencing
  • patients without genetic diagnosis are also at risk of Charcot-Marie-Tooth disease. It amounts to about 30% of Additionally, clinical research on genetic treatments for Charcot-Marie-Tooth disease has recently been conducted, emphasizing the importance of accurate diagnosis of Charcot-Marie-Tooth disease.
  • Nerve biopsy is also an invasive test and has limitations in being used as a diagnostic test every time.
  • Biomarkers are indicators that can detect changes in the body using proteins, DNA, RNA, metabolites, etc. By using biomarkers, you can objectively measure the subject's normal or pathological state and degree of response to drugs. You can. Biomarkers are called the internal phenotype of a specific disease and can be used to find the cause of a specific disease or measure the risk of developing it.
  • TMPRSS5 neurofilament (NFL) or Schwann cells, which is detected at a higher rate in patients with Charcot-Marie-Tooth disease compared to non-patients.
  • a composition for diagnosing Charcot-Marie-Tooth disease comprising an agent for detecting the expression of p62 protein in serum or plasma.
  • composition for diagnosing Charcot-Marie-Tooth disease according to 1 above, wherein the Charcot-Marie-Tooth disease is selected from the group consisting of demyelinating type, axonal type, and intermediate type.
  • a kit for diagnosing Charcot-Marie-Tooth disease comprising the composition of any one of 1 or 2 above.
  • a method of providing information for diagnosing Charcot-Marie-Tooth disease which provides information that when the p62 protein concentration in serum or plasma isolated from an individual is higher than that of the control group, the individual has a higher probability of developing Charcot-Marie-Tooth disease compared to the control group.
  • a method of providing information for diagnosing Charcot-Marie-Tooth disease which provides information that the individual has developed Charcot-Marie-Tooth disease when the p62 protein concentration in serum or plasma isolated from the individual is higher than 229.4 pg/ml.
  • Charcot-Marie-Tooth disease diagnosis which provides information that if the p62 protein concentration in serum or plasma isolated from a patient with Charcot-Marie-Tooth disease is higher compared to the control group, the patient is more likely to have severe Charcot-Marie-Tooth disease compared to the control group How to provide information for .
  • the diagnostic composition and kit of the present invention can diagnose Charcot-Marie-Tooth disease in a non-invasive manner.
  • the method of the present invention is non-invasive and can provide information for diagnosing or determining the severity of Charcot-Marie-Tooth disease in a simple manner.
  • composition/method of the present invention can diagnose Charcot-Marie-Tooth disease with high accuracy or provide information necessary for diagnosis.
  • Figure 1 shows the results of an experiment on the level of p62 protein expression in patients with Charcot-Marie-Tooth disease compared to non-patients.
  • Figure 2 shows the results of an experiment on the level of p62 protein expression by Charcot-Marie-Tooth disease severity, onset period, and age.
  • Figure 3 shows the results of an experiment on the level of p62 protein expression according to severity in different subtypes according to gene type of Charcot-Marie-Tooth disease.
  • Figure 4 shows the results of an experiment on the level of p62 protein expression in muscle cells of C22 mice compared to WT mice.
  • Figure 5 shows the results of an experiment on the level of p62 protein expression in the sciatic nerve and Schwann cells of C22 mice compared to WT mice.
  • the present invention relates to a composition for diagnosing Charcot-Marie-Tooth disease.
  • composition for diagnosing Charcot-Marie-Tooth disease of the present invention includes an agent for detecting the expression of p62 protein in serum or plasma.
  • the present inventors designed the present invention based on the finding that the concentration of p62 protein in serum or plasma is positively correlated with the occurrence of Charcot-Marie-Tooth disease, and that the higher the concentration, the higher the severity of the disease.
  • composition of the present invention contains an agent for detecting the expression of p62 protein in serum or plasma, and can be used to measure the presence and concentration of p62 protein in serum or plasma, thereby diagnosing the occurrence of Charcot-Marie-Tooth disease or , can be used to diagnose its severity.
  • the p62 protein concentration in the serum or plasma of patients suspected of Charcot-Marie-Tooth disease with the concentration in the non-patient control group, if the p62 protein concentration in the serum or plasma of the patient suspected of Charcot-Marie-Tooth disease is higher in the non-patient control group, Compared to other cases, it can be diagnosed that the probability of developing Charcot-Marie-Tooth disease is higher.
  • the patient with the higher concentration of the protein can be diagnosed as more likely to have developed Charcot-Marie-Tooth disease or as having more advanced symptoms.
  • agent for detecting the expression of a protein in serum or plasma is not limited as long as it can detect it by interacting with p62, such as by binding to or reacting with the p62 protein in serum or plasma.
  • agent may be an antibody, aptamer, protein, peptide, nucleic acid, polymer, compound, or reagent.
  • Charcot-Marie-Tooth disease may be selected from the group consisting of demyelinating, axonal, and intermediate types. For example, it may be CMT1A in the demyelinating type, CMT2A in the axonal type, or CMTX1 in the intermediate type, but is not limited thereto.
  • the present invention relates to a kit for diagnosing Charcot-Marie-Tooth disease comprising the composition.
  • the kit not only includes a material that specifically binds to or reacts with the p62 protein, but may also include one or more additional compositions, components, devices, etc. suitable for an analysis method for measuring the protein expression level.
  • Analytical methods include, for example, BCA (Bicinchoninic acid) assay, Biuret reaction assay, Lowry test (Folin-Ciocalteau), Bradford assay, ultraviolet spectrophotometry, such as the Warburg-Christian method or Waddell method, and Micro-Kjeldahl assay. Alternatively, a combination of these may be used, but is not limited thereto, and protein analysis methods commonly used in the art may be used.
  • the kit includes an antibody that specifically binds to the p62 protein, a secondary antibody conjugate conjugated with a label that develops color by reaction with the substrate, a chromogenic substrate solution for color development with the label, a washing solution, and an enzyme reaction stopping solution. It may include, and may be manufactured into a number of separate packaging or compartments containing the reagent components used, but is not limited thereto.
  • the kit may include, but is not limited to, a substrate, an appropriate buffer solution, a secondary antibody labeled with a detection label, and a chromogenic substrate for immunological detection of antibodies.
  • the kit may be a kit characterized by including essential elements necessary for performing ELISA in order to implement various ELISA methods such as an ELISA kit and a sandwich ELISA kit.
  • These ELISA kits contain specific antibodies against the proteins.
  • the antibody has high specificity and affinity for the P62 protein and has little cross-reactivity to other proteins, and may be a monoclonal antibody, polyclonal antibody, or recombinant antibody.
  • ELISA kits may include antibodies specific for control proteins.
  • Other ELISA kits may include reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes and their substrates, or other substances capable of binding to antibodies. It may not be limited to this.
  • the kit may be a kit for implementing Western blot, immunoprecipitation analysis, complement fixation analysis, flow cytometry, or protein chip, and may further include additional components suitable for each analysis method.
  • Charcot-Marie-Tooth disease can be diagnosed by comparing the amount of antigen-antibody complex formation.
  • the present invention relates to a method of providing information for diagnosing Charcot-Marie-Tooth disease.
  • the method of the present invention provides information that when the p62 protein concentration in serum or plasma isolated from an individual is high compared to the control group, the individual has a higher probability of developing Charcot-Marie-Tooth disease compared to the control group.
  • the subject may be an animal suspected of having Charcot-Marie-Tooth disease, another animal for which information for Charcot-Marie-Tooth disease diagnosis is to be provided, and the animal may be a mammal, including a human.
  • the control group may be, for example, a non-patient with Charcot-Marie-Tooth disease, and the p62 protein concentration in the serum or plasma of the subject may be compared with the p62 protein concentration in the serum or plasma of the subject, or the mean value, median value, etc. of the group including them. It may be possible.
  • the p62 protein concentration in serum or plasma is higher than in other cases. Therefore, if the p62 protein concentration in the serum or plasma of the subject is higher than that of the control group, the probability of the subject developing Charcot-Marie-Tooth disease compared to the control group is higher. It can provide information that it is high.
  • the method of the present invention may further include measuring the p62 protein concentration in serum or plasma isolated from the subject and comparing it with the concentration in the control group.
  • the concentration measurement can be performed, for example, using the composition described above, and methods known in the art for measuring protein concentration can be used without limitation.
  • the present invention relates to a method of providing information for diagnosing Charcot-Marie-Tooth disease, which provides information that the individual has developed Charcot-Marie-Tooth disease when the p62 protein concentration in serum or plasma isolated from the individual is higher than 229.4 pg/ml. will be.
  • the p62 protein concentration value of 229.4 pg/ml in the serum or plasma is a cutoff value to distinguish between patients with Charcot-Marie-Tooth disease and the non-patient group. If the p62 protein concentration in the serum or plasma of an individual is higher than 229.4 pg/ml, the individual has Charcot-Marie-Tooth disease. It can provide information that maritus disease has occurred.
  • the method of the present invention may further include the step of measuring the p62 protein concentration in serum or plasma isolated from the subject, the description of which is as described above.
  • the present invention provides a Charcot-Marie-Tooth disease diagnosis that provides information that when the p62 protein concentration in serum or plasma isolated from a Charcot-Marie-Tooth disease patient is higher than that of the control group, the patient is more likely to have severe Charcot-Marie-Tooth disease compared to the control group. It is about how to provide information for.
  • Patients with Charcot-Marie-Tooth disease include animals with Charcot-Marie-Tooth disease or other animals seeking information for diagnosing Charcot-Marie-Tooth disease, and the animals may be mammals, including humans.
  • the control group may be, for example, a patient with Charcot-Marie-Tooth disease, and the p62 protein concentration in the serum or plasma of the subject is compared with the p62 protein concentration in the serum or plasma of the control patient, or the average value, median value, etc. of the control patient are compared. It may be possible.
  • the severity of Charcot-Marie-Tooth disease can be divided according to the degree of symptom expression due to the disease, and the higher the degree of symptom expression, the higher the severity of Charcot-Marie-Tooth disease.
  • These symptoms may include, for example, extremity muscle weakness and atrophy, neurogenic muscular atrophy, inhibition of autophagy in muscle, denervation-induced muscle loss, progressive muscle wasting, etc.
  • the severity of Charcot-Marie-Tooth disease can be measured using the CMT neuropathy score version 2 (CMTNSv2), with CMTNSv2 ⁇ 10 being mild, CMTNSv2 being 11-20 being moderate, and CMTNSv2 being ⁇ 21 being severe. It can be divided into three groups:
  • the Charcot-Marie-Tooth disease scoring system is not limited to this, and systems such as CMTPedS, CMT-FOM, or CMTInfS may be used.
  • the p62 protein concentration in serum or plasma is higher than in other cases, and the higher the degree of expression of the above symptoms, for example, the higher the CMTNSv2 value, the higher the p62 protein concentration in serum or plasma. If the p62 protein concentration in the patient's serum or plasma is higher than that of the control group, information may be provided that the patient is more likely to have severe Charcot-Marie-Tooth disease compared to the control group.
  • the method of the present invention may further include measuring the p62 protein concentration in serum or plasma isolated from the patient and comparing it with the concentration in the control group.
  • the concentration measurement can be performed, for example, using the composition described above, and methods known in the art for measuring protein concentration can be used without limitation.
  • the difference in p62 levels in the plasma of CMT patients and healthy controls (HC) was compared using ELISA using the p62-containing biomarker composition of the present invention.
  • plasma p62 levels in CMT patients and age-matched healthy controls were measured using ELISA to determine whether the plasma p62 concentration could be changed in CMT patients.
  • CMT patients were consecutively enrolled after approval from the Hereditary Neuropathy Clinic, Department of Neurology, Samsung Medical Center. Written consent was obtained from all participants according to a protocol approved by the Bioethics Committee (IRB) of Sungkyunkwan University Samsung Seoul Hospital (SMC, 2020-01-146). PMP22 replication causing CMT1A was determined by hexaplex microsatellite PCR on the chromosome 17p12 region. Other mutations were screened using whole exome sequencing and confirmed using Sanger sequencing. All CMT patients had confirmatory causative gene mutations (Table 1). Disease severity was measured using CMTNSv2. CMT patients were divided into three groups according to disease severity: mild (CMTNSv2 ⁇ 10), moderate (CMTNSv2, 11-20), and severe (CMTNSv2 ⁇ 21).
  • Demographic data, median p62 plasma concentration, CMTNSv2 and INCAT scores of CMT patients and HCs Patient group n Age(y) (SEM) Sex,F/M Duration (SEM) p62, pg/mL (IQR) CMTNSv2 (IQR) INCAT (IQR) CMT 138 44.90 (1.174) 58/80 22.67 (1.372) 2354 (1603-3622) 14.0 (9-18) N.A. Control 59 44.88 (1.069) 30/29 N.A. 1978 (1139-2522) N.A. N.A.
  • CMT4H One 26 0/1 20 4666 18 N.A.
  • CMT2EE One 31 0/1 18 3597 18 N.A.
  • CMT2F 2 37.5 (5.5) 0/2 16 (4) 899 (788-1011) 10.5 (10-11) N.A.
  • CMT2O One 45 0/1 20 3459 17 N.A.
  • CMT2S One 33 0/1 One 2282 10 N.A.
  • CMT2U One 63 1/0 5 5203 19 N.A.
  • HC plasma collection from HC
  • subjects who visited Dong-A University Hospital for health examination and matched in gender and age to the CMT group were enrolled.
  • Exclusion criteria included anemia, liver or kidney damage, or elevated fasting plasma glucose levels, which may contribute to peripheral neuropathy. Those with neurological symptoms or history of neurological disease were excluded.
  • Antibodies against p62, glyceraldehyde 3-phosphate dehydrogenase, and myelin basic protein (MBP) were purchased from Abcam (Cambridge, UK). Antibodies against neurofilament chain medium (NF-M) and ⁇ -actin were obtained from Thermo Fisher Scientific (Waltham, MA, USA) and Santa Cruz biotechnology (CA, USA), respectively. Horseradish peroxidase (HRP)-linked anti-rabbit IgG was purchased from Cell Signaling Lab (Beverly, MA, USA). Alexa Fluor 488 or Cy3-conjugated secondary antibodies were purchased from Molecular probes (Carlsbad, CA, USA). Unless otherwise specified, all other reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA).
  • Blood samples were collected and processed within 1 hour. Blood was collected in SST tubes, centrifuged at 3,000 rpm for 10 minutes at 4°C, and plasma was aliquoted and stored at -80°C.
  • Measurement of plasma p62 was performed using a commercially available ELISA kit (LSbio, LS-F49427, Seattle, USA). All samples were analyzed in triplicate without dilution according to the manufacturer's instructions. For samples with an average p62 concentration of 2354 pg/ml, the average repeatability coefficient of variation was 7.31% and the inter-assay coefficient of variation was 8.78%. The limit of detection determined by the mean blank signal +3 SD for the p62 assay was 51.19 pg/ml. The lower limit of quantification (LLOQ), measured as the mean blank signal +10 SD, was 173.5 pg/ml. All samples in which p62 was detected under LLOQ were considered to have a concentration of 0.
  • LLOQ lower limit of quantification
  • C22 mice [B6; CBACa-Tg(PMP22)C22Clh/H] was purchased from Samsung Seoul Hospital.
  • the mouse model contains seven copies of the human Pmp22 gene, which causes demyelinating neuropathy.
  • Control C57BL/6 mice and C22 mice were perfusion-fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS), and the sciatic nerve and gastrocnemius muscle were collected and cryoprotected in a 20% sucrose solution.
  • PBS phosphate-buffered saline
  • sections with a thickness of 10 ⁇ m were made using a cryocut machine and stored in the freezer until use. Slides were blocked with PBS containing 0.2% Triton X-100 and 5% bovine serum albumin for 1 hour at room temperature. Next, the slides were incubated with primary antibodies at 4°C overnight and then washed three times with PBS.
  • p62-positive myocytes were defined as myocytes with five or more p62 spots.
  • the cytoplasmic area of 300 p62-positive and 300 p62-negative myocytes randomly selected from 3 animals in each group was measured. A total of nine sections from three animals in each group were used to determine the number of p62-positive myocytes.
  • tissue lysates were prepared using a TissueLyser LT (Qiagen) in modified RIPA buffer containing 1% Triton X-100 in Tris-EDTA solution. .
  • the RIPA lysate was centrifuged at 9000 g for 10 min at 4°C and the supernatant was collected. Proteins (10-35 ⁇ g) were separated by SDS-PAGE and then transferred to nitrocellulose membranes (Amersham Biosciences). After blocking for 1 hour at room temperature with Tris-buffered saline (TBST; pH.
  • the membrane was incubated with primary antibody (1:500) in TBST containing 1% nonfat dry milk. -2000) and cultured at 4°C overnight. After washing three times with TBST, the membrane was incubated with HRP-conjugated secondary antibody for 1 hour at room temperature. Chemiluminescence reactions were performed using the ECL Western blotting detection system (GE Healthcare). Images were then detected using Luminogragh 3 and quantified with CS Analyzer 4 (ATTO). Quantification was performed with a density analyzer in CS Analyzer 4, and values were obtained from three independent experiments.
  • Results were expressed as median ⁇ standard error of the mean (SEM).
  • ELISA data were analyzed using one-way analysis of variance followed by Kruskal-Wallis test and Sidak's multiple comparison test using GraphPad Prism version 9 (GraphPad Software Inc., La Jolla, CA). Correlation was assessed using Spearman and Pearson correlation coefficients, and comparisons of plasma p62 concentrations between the two groups were analyzed using the Mann-Whitney U test. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to evaluate the diagnostic performance of plasma p62 in CMT patients.
  • ROC receiver operating characteristic
  • CMT1A 70
  • CMTX1 25
  • CMT2A 11
  • the median plasma p62 concentration of HC was 1978 pg/ml, and the median plasma p62 concentration of CMT patients was 2354 pg/ml (p ⁇ 0.001; Table 1 and Figure 1A).
  • High plasma p62 levels were observed in all subtypes of CMT (demyelinating, axonal, or intermediate). Plasma p62 levels were higher in demyelinating and axonal types of CMT than in HC, the most common genetic subtype. There was a significant increase in CMT1A.
  • CMT is a chronic neuropathy that can cause secondary muscle atrophy with disease progression in all subtypes of CMT
  • p62 was analyzed in the gastrocnemius muscle of WT mice and C22 mice, an animal model of CMT1A, at 9 and 24 weeks after birth. expression was investigated. Western blot analysis showed that p62 expression levels in muscle lysates increased with age in C22 mice compared to WT mice ( Figures 4A and B). Detection of p62 protein in C22 gastrocnemius muscle cells using immunofluorescence staining showed an increase in p62 spot staining in 24-week-old C22 mice, which is indicated by an arrow ( Figure 4C).
  • Muscle atrophy in C22 mice is known to be caused by neurological dysfunction. Therefore, we tested whether p62 can induce axotomy-induced muscle atrophy in wild-type C57BL/6 mice and showed that p62 expression was induced in the gastrocnemius muscle 4 weeks after sciatic nerve axotomy ( Fig. 4E and F ). Together, this indicates that atrophic muscles due to neurological dysfunction may provide a potential cause for elevated plasma p62.

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Abstract

La présente invention concerne une composition pour le diagnostic de la maladie de Charcot-Marie-Tooth et un procédé de fourniture d'informations pour le diagnostic de celle-ci. La composition peut être efficacement utilisée pour diagnostiquer la maladie de Charcot-Marie-Tooth et déterminer sa sévérité, par détection de la protéine p62 dans le sérum ou le plasma et par mesure de sa concentration pour la comparer à un groupe témoin.
PCT/KR2022/006439 2022-05-04 2022-05-04 Composition pour le diagnostic de la maladie de charcot-marie-tooth et procédé de fourniture d'informations pour le diagnostic de celle-ci WO2023214599A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US5306616A (en) * 1991-06-06 1994-04-26 Baylor College Of Medicine Molecular diagnosis of autosomal dominant charcot-marie-tooth disease
WO2011061304A1 (fr) * 2009-11-20 2011-05-26 Pharnext Nouveaux outils de diagnostic pour la maladie de charcot-marie-tooth
KR20180026990A (ko) * 2016-09-05 2018-03-14 사회복지법인 삼성생명공익재단 샤르코 마리 투스병 치료용 약학 조성물
KR101967880B1 (ko) * 2017-08-09 2019-04-10 사회복지법인 삼성생명공익재단 샤르코-마리-투스병 진단용 마커 및 그의 용도

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JP6537095B2 (ja) * 2014-10-24 2019-07-03 国立大学法人 筑波大学 癌の再発及び／又は転移の予測診断用マーカー
KR101924269B1 (ko) * 2016-12-30 2018-11-30 재단법인대구경북과학기술원 근위축성 측삭경화증의 예방, 경감 또는 치료를 위한 방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5306616A (en) * 1991-06-06 1994-04-26 Baylor College Of Medicine Molecular diagnosis of autosomal dominant charcot-marie-tooth disease
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