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WO2008138475A1 - Utilisation de crmp1 en tant que marqueurs pour des maladies ppsychiatriques chroniques et anticoprs monoclonaux contre crmp1 - Google Patents

Utilisation de crmp1 en tant que marqueurs pour des maladies ppsychiatriques chroniques et anticoprs monoclonaux contre crmp1 Download PDF

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Publication number
WO2008138475A1
WO2008138475A1 PCT/EP2008/003407 EP2008003407W WO2008138475A1 WO 2008138475 A1 WO2008138475 A1 WO 2008138475A1 EP 2008003407 W EP2008003407 W EP 2008003407W WO 2008138475 A1 WO2008138475 A1 WO 2008138475A1
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WO
WIPO (PCT)
Prior art keywords
crmp1
marker
depression
insoluble
schizophrenia
Prior art date
Application number
PCT/EP2008/003407
Other languages
German (de)
English (en)
Inventor
Carsten Korth
Verian Bader
Original Assignee
Carsten Korth
Verian Bader
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Carsten Korth, Verian Bader filed Critical Carsten Korth
Publication of WO2008138475A1 publication Critical patent/WO2008138475A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/302—Schizophrenia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression

Definitions

  • the invention relates to a novel marker for chronic psychiatric disorders, in particular schizophrenia, bipolar disorder or depression.
  • Chronic psychiatric disorders are among the most common diseases with lifetime prevalence rates of about 1% for schizophrenia and bipolar disorder and up to 10% for depression.
  • a test is known in which the activity or concentration of phospholipase (cPLA.sub.2) is measured. Increases in the measured values from normal values are indicative of bipolar disorders, e.g. Taken schizophrenia.
  • cPLA.sub.2 phospholipase
  • US Pat. No. 4,874,694 describes the gel electrophoretic measurement of phospho-protein patterns for the diagnosis of neurological diseases, e.g. Schizophrenia.
  • U.S. Patent Application 20050208519 relates to biomarker combinations that can be used in the diagnosis of schizophrenia. These are certain genes and their products, e.g. the genes of ADSS, APOBEC3B, (ATM); (CLC), CTBPl, C-X-C, (CXCLI), etc.
  • US Patent Application 20050089927 relates to specific short peptides which are selectively bound by samples from schizophrenic patients while in Samples from non-schizophrenic patients show little or no binding.
  • WO 2005/077978 proposes a method with which biological markers for bipolar disorders can be identified.
  • a protein fraction is obtained in a first step from brain samples of diseased patients, enriched in the insoluble proteins.
  • this protein fraction by conventional means, e.g. by immunization of animals, antibodies produced.
  • Antibodies which appear to be suitable are determined for the proteins recognized by them, the theory being that these proteins, if they are specifically present only in diseased patients in insoluble form, are suitable as markers.
  • the object of the invention is to provide, starting from the known method, a marker with which a safer diagnosis of chronic psychiatric diseases such as e.g. Schizophrenia, bipolar disorder, and depression and a possible re-definition of such diseases is possible.
  • chronic psychiatric diseases such as e.g. Schizophrenia, bipolar disorder, and depression and a possible re-definition of such diseases is possible.
  • the invention is based on polypeptides contained in insoluble brain regions, which are recognized by a monoclonal antibody with the internal name mAb 6HI 1 isolated in the context of the invention.
  • Advantageous embodiments of the invention are specified in the subclaims.
  • the antibody mAb 6HI 1 is segregated from a hybridoma cell line deposited by the applicant on April 4, 2007 under the number DSM ACC2836 with the DSMZ German Collection of Microorganisms and Cell Cultures GmbH.
  • An essential aim of the use according to the invention is therefore to define a new subset of patients suffering, for example, either "schizophrenia, bipolar disorder or recurrent depression" via the polypeptide serving as a marker.
  • a common feature of this, and possibly other patients who have not yet been examined in this chronic psychiatric Diseases suffer from, is that at least one of the antibodies recognized by the antibody mAb 6Hl 1 polypeptides in the brain becomes insoluble or aggregated.
  • the marker for diagnosis and accompanying medical therapy serves to monitor the progress of the diseases defined via it.
  • the antibody mAb 6HI 1 recognizes essentially 3 proteins with molecular weights of 54 kDa, 62 kDa and about 74 kDa,
  • the two larger proteins are splice variants of the protein CRMP1 (collapsin response mediator protein 1) (see eg with respect to the 55 kDa variant example 2), while the smaller 54 kDa band either represents a hitherto unknown smaller splice variant or a degradation product of the two higher variants is.
  • the protein CRMP1 is specific at a number of times z. established disease patterns across subset of chronic psychiatric disorders becomes insoluble, aggregated, and thus can be used as a specific biological marker for these disorders.
  • CRMP1 protein or a specific fragment of CRMP1 is used as the marker.
  • the CRMP1 gene currently has two transcripts expressed in proteins of different length (splice variants), the long form CRMP1-I has 686 amino acids, the short form CRMP 1-2 572 amino acids.
  • the amino acid sequences of both variants are shown in FIG. 1 (CRMP1-I, 74 kDa) and FIG. 2 (CRMP1-2, 62 kDa) and in SEQ ID NO: 1 (CRMP1-I, 74) and SEQ ID NO: 3 (CRMP 1-2).
  • the gene sequences are shown in SEQ ID NO: 2 (CRMP1-I) and SEQ ID NO: 4 (CRMP1-2).
  • the use of the indication CRMP1 in this application is intended to cover all variants occurring in vivo, including various splice forms and polymorphism-induced mutations of this protein, and at the protein level conformations, degradation forms, or other post-translationally altered forms, such as phosphorylated forms. Furthermore, the indication CRMP1 should also include fragments which can be detected in tissue samples and clearly assigned to CRMP1.
  • the invention relates to the use of the protein CRMP1, its splice forms, and fragments, as well as the associated gene as a marker for the classification and diagnosis of chronic psychiatric disorders, in particular schizophrenia, bipolar disorders or depression, or clarifying whether a predisposition to these diseases exists , for the evaluation of drugs in the context of a therapy control, as well as appropriate procedures.
  • the CRMP1 protein in general, or specific degradation products can be used as markers.
  • a specific degradation pattern of CRMP1 could also be disease-specific and be detected by protein-biochemical methods capable of recognizing specific fragments.
  • the insoluble version has different degradation patterns than the soluble one, since other targets within the same polypeptide sequence are available for degrading proteases. It is therefore conceivable that disease-specific CRMPl is degraded differently than CRMPl in healthy or not predisposed persons. In this case, a different degradation pattern can occur. It is conceivable, for example, that in diseased or predisposed persons a particular fragment is clearly enriched, which is e.g. could be detected by the use of specific antibodies or other appropriate methods.
  • CRMP1 should also include polymorphisms or mutated versions in addition to the splice forms and fragments mentioned. It is conceivable that the insolubility of CRMP1 can be genetically engineered e.g. B. is determined by polymorphisms or mutations in the CRMPl gene. Examination of the CRMPl gene for such deviations may therefore allow a routine nescreening or an estimation of the disease risk or in case of diseased persons a safe and fast diagnosis.
  • CRMP1 as a marker, regardless of whether the protein is dissolved or in insoluble form.
  • the insoluble variant presumably due to a misfolding associated with the disease is deliberately used as a marker. Detection may be via an antibody that specifically recognizes the insoluble variant of CRMP1.
  • the tissue used as a sample material is biochemically purified in such a way that the insoluble CRMP form, if present, is enriched and can then be detected.
  • insoluble CRMP1 tends to form aggregates, which in turn may be detected macroscopically.
  • Suitable tissues for detection are eg blood, cerebrospinal fluid or brain. Depending on the tissue used, the purification is carried out in different ways known to those skilled in the art. Alternative tissues or tissue fluids are also available for the diagnostic isolation of CRMP1 or its gene, such as saliva, tears, urine; The removal of skin or muscle biopsies is also conceivable. With suitable ligands which detect CRMP1 and are labeled, for example, with fluorescent dyes, it is also possible, if appropriate after their application of a patient to be tested with non-invasive methods, to test them. which, like an ophthalmoscope, attempts to detect aggregated CRMPl in the ocular fundus.
  • CRMP1 is also referred to in the literature as dihydropyriminidase related protein 1 (DRP1).
  • DRP2 dihydropyriminidase related protein 1
  • a related protein of the same family are described in the literature (Johnston-Wilson et al., 2000, Molecular Psychiatry 5: 142-149, Hong et al., 2005, American Journal of Medical Genetics, Part B (Neuropsychiatric Genetics). 136B: 8-11) compounds for schizophrenia.
  • no significant association of the DRP2 protein with schizophrenia, depression or bipolar disease could be found in the insoluble brain fraction of post mortem material in our own investigations in FIG.
  • CRMP1 as a marker has the following advantages over the prior art:
  • the advantage of CRMP1-based diagnostics is that the marker is specific, in contrast the detection of phospholipase is suggested, as for example in US Pat. No. 7,015,006.
  • the invention also relates to a method for diagnosing psycchiatrical diseases such as bipolar disorders schizophrenia and recur-
  • the method is based in one embodiment on the fact that from a suitable tissue sample of a patient, a fraction is purified, enriched in the insoluble proteins. In this fraction, then by means of e.g. An antibody test checks whether CRMPl is present or not. The positive case is indicated as an indication of the presence of e.g. Assessed schizophrenia or depression.
  • An advantage of this embodiment is that an antibody can be used, the CRMPl generally recognizes, ie in the soluble as well as the insoluble variant, since it can be assumed that in the examined fraction only the insoluble variant is present.
  • insoluble CRMP1 It has not yet been conclusively clarified why the increased occurrence of insoluble CRMP1 is causally linked to eg schizophrenia or depression. Furthermore, it is very likely that the formation of insoluble variants of the CRMP1 is genetically predisposed, eg in the form of polymorphisms or the like. To date, all protein aggregates identified in chronic brain disease processes have been identifiable in familial forms of specific diseases as well as in sporadic forms (Prusiner, 2001, New England Journal of Medicine 344: 1516-1526). The human CRMPl gene is located on chromosome 4pl6. Genetic changes in this region are associated with a risk of developing psychiatric disorders (Als et al., 2004, Molecular Psychiatry 9: 93-98).
  • the gene coding for CRMP1 is isolated from a tissue sample from a patient and checked for the presence of polymorphisms, mutations, etc., where possible polymorphisms or mutations speak for a disease or a predisposition.
  • a further embodiment of the invention therefore provides that the gene coding for CRMP1 is examined for the presence of genetic deviations from the standard sequence and in particular detected polymorphisms are taken as an indication for a predisposition of the named diseases.
  • drugs can be tested for their effectiveness.
  • the procedure can be carried out with different tissue samples. Genetic sequence studies may use any sample that allows the isolation of DNA. In protein level studies, all tissue materials are suitable in which an antibody test for CRMP1 or its fragments can be performed.
  • CRMPI aggregate-specific ligands for example antibodies, are produced, which then selectively bind the insoluble CRMP1 and not the soluble CRMP1.
  • CRMPl bind and are thus disease-specific without the need for the previous biochemical purification.
  • CRMPl insolubility of CRMPl during the disease process in schizophrenia, bipolar disorder or recurrent depression interferes with binding proteins. This can lead to a loss of binding partners or an increase in binding partners.
  • the loss of the known CRMPl binding partners Axinl, Rockl, Cdk5, GSK3, CRMP2, PlexAl, Fyn, reelin, neurotrophin could thus be diagnostically relevant for schizophrenia, bipolar disorder or depression.
  • the determination of corresponding protein concentrations parallel to the CRMP1 could therefore be useful.
  • the simultaneous occurrence of polymorphisms in the CRMP1 gene AND in one of the genes of the interaction partners can be particularly disease-relevant.
  • inventive novelty described herein of being able to diagnose insoluble CRMP1 as a marker for psychiatric disorders also makes it possible to provide this diagnostic as a method for new causal screening assays to identify novel drugs for patients with schizophrenia, bipolar disorder or recurrent depression.
  • an assay can be developed in which insoluble CRMP1 is produced in a cell line, such as by overexpression and / or insertion of appropriate mutations or polymorphisms of CRMP1; Therapeutic substances may then be tested by addition to the cell culture medium when the disappearance of the insoluble CRMP1 is then measured by the inventive assay.
  • a transgenic organism for example a mouse, which expresses a gene which, for example by adding mutations, produces a particularly high amount of insoluble CRMP1; Therapeutic substances to be tested are then administered to the animal in an appropriate manner and the disappearance of the insoluble CRMP1 measured.
  • This measurement can be carried out, for example, by biochemical fractionation of the insoluble proteins and subsequent detection with CRMP1 antibodies, for example mAb 6HI 1.
  • CRMP1 antibodies for example mAb 6HI 1.
  • it may also be attempted to simulate the insolubility of CRMP1 in vitro, such as by expression of appropriate CRMP1 constructs in Escherichia coli and corresponding refolding in vitro, and testing the concomitant addition of therapeutic substances.
  • FIG. 3 shows western blots of the aggregate (misfolded protein fractions) of 60 brains of patients with schizophrenia (S), depression (D), bipolar disorder (B), or no brain disease (-).
  • the immunoreactivity for mAb 6HI 1 to CRMP1 can be seen above, in each case the immunoreactivity for DRP-2 (also called CRMP2) as comparison below.
  • the blot shows a specific reactivity of a monoclonal antibody labeled mAb6HI1 with a subset of patients with schizophrenia, depression, or bipolar disorder (underlined cases), which is not true for the reactivity of the DRP-2 antiserum, as it also reacts with false positives.
  • Fig. 4 shows a scheme of identification of the mAb 6HI 1 antigen by means of protein chips. On an array of recombinantly expressed proteins, mAb 6HI 1 reacts only with individual proteins, which are individually recombined in the sequence. nant be expressed and incubated on the Western blot with mAb 6Hl 1 (see Figure 3).
  • FIG. 5 documents the expression of various clones identified as positive on the protein chip in E. coli and their reactivity in the Western blot with mAb 6HI 1 (right).
  • mAb 6HI 1 (right).
  • the second line it can be seen that the clone corresponding to the CRMP1 gene reacts most strongly with mAb 6H1.
  • Fig. 6 shows a size separation of a schizophrenia brain homogenate with mAb 6HI lim Western blot.
  • mAb 6HI 1 shows immunoreactivity in different fractions, i.a. in a fraction at about 54 kDa (lines 8 and 9), and in higher-running multimeric fractions (lines 5 to 7, about 62 kDa) or as long CRMPl at about 74 kDa (lines 1 to 3).
  • the individual aggregate fractions of the 60 brains were then separated by SDS gel electrophoresis, blotted and incubated with the mAb 6Hl 1. It was shown that the mAb 6Hl 1 recognizes an antigen which is 75-55 kDa in various forms and is specific in the aggregation of patients with schizophrenia, bipolar disorder or depression (FIG. 3).
  • mAb 6HI 1 insoluble CRMP1 could be identified in a collection of 60 brains in the following cases: 4 bipolar disorders, 3 depression, 2 schizophrenia. No normal brains were found to be false positives with mAb 6Hl 1, so the specificity is 100% and the ability to identify patients with chronic psychiatric illness has been proven. Subgroups of the disease phenotypes bipolar disorder, depression and schizophrenia were identified. Recent studies show a variability of psychiatric disease phenotypes with the same genotype, which explains the overlaps that have been identified here in the phenomenological diagnosis of the disease
  • the hybridoma cell line which secretes the antibody 6HI 1 was deposited on April 4, 2007 under the number DSM ACC2836 with the DSMZ German Collection of Microorganisms and Cell Cultures GmbH, Inhoffenstrasse 7B, 38124 Braunschweig.

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Abstract

L'invention concerne des CRMP1 ou le gène codé pour ceux-ci en tant que marqueur pour des maladies psychiatriques chroniques, en particulier la schizophrénie, les troubles bipolaires ou la dépression.
PCT/EP2008/003407 2007-05-11 2008-04-26 Utilisation de crmp1 en tant que marqueurs pour des maladies ppsychiatriques chroniques et anticoprs monoclonaux contre crmp1 WO2008138475A1 (fr)

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DE200710022669 DE102007022669A1 (de) 2007-05-11 2007-05-11 Verwendung von CRMP1 als Marker für chronisch psychiatrische Erkrankungen
DE102007022669.3 2007-05-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013040502A3 (fr) * 2011-09-14 2013-05-10 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Procédés et trousses permettant la détection et la surveillance de biomarqueurs de diagnostic pour le trouble de stress post-traumatique (tspt) et permettant de distinguer la forme suicidaire et la forme non suicidaire du trouble

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
DE102008016064A1 (de) 2008-03-26 2009-10-01 Carsten Dr. Korth Verfahren zur Diagnose und Behandlung von chronisch psychiatrischen Erkrankungen sowie Marker und Targets für solche Verfahren

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WO2005077978A2 (fr) * 2004-02-13 2005-08-25 Heinrich-Heine-Universität Düsseldorf Anticorps destines au diagnostic et au traitement de maladies neuropsychiatriques, notamment de la schizophrenie, de la depression et de troubles affectifs bipolaires

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S. BRETIN ET AL.: "Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain.", THE JOURNAL OF COMPARATIVE NEUROLOGY, vol. 486, no. 1, 23 May 2005 (2005-05-23), U.S.A., pages 1 - 17, XP002494156 *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013040502A3 (fr) * 2011-09-14 2013-05-10 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Procédés et trousses permettant la détection et la surveillance de biomarqueurs de diagnostic pour le trouble de stress post-traumatique (tspt) et permettant de distinguer la forme suicidaire et la forme non suicidaire du trouble
CN103959067A (zh) * 2011-09-14 2014-07-30 促进军事医学的亨利·M·杰克逊基金会公司 用于检测和监测用于创伤后应激障碍（ptsd）的诊断生物标志物以及用于区分自杀式与非自杀式障碍的方法和试剂盒
AU2012308305B2 (en) * 2011-09-14 2017-11-23 Banyan Biomarkers, Inc. Processes and kits to detect and monitor for diagnostic biomarkers for post traumatic stress disorder (PTSD) and to differentiate between suicidal and non-suicidal form of the disorder

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