WO2001096878A2 - Marqueur pour maladies neurodegeneratives et son utilisation pour le criblage de medicaments diriges contre lesdites maladies - Google Patents

Marqueur pour maladies neurodegeneratives et son utilisation pour le criblage de medicaments diriges contre lesdites maladies Download PDF

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Publication number
WO2001096878A2
WO2001096878A2 PCT/BE2001/000100 BE0100100W WO0196878A2 WO 2001096878 A2 WO2001096878 A2 WO 2001096878A2 BE 0100100 W BE0100100 W BE 0100100W WO 0196878 A2 WO0196878 A2 WO 0196878A2
Authority
WO
WIPO (PCT)
Prior art keywords
disease
neurodegenerative disease
disorder
hybridisation
protein
Prior art date
Application number
PCT/BE2001/000100
Other languages
English (en)
Other versions
WO2001096878A3 (fr
Inventor
Roland Pochet
Bernhard Keller
Claus Heizmann
Original Assignee
University Of Zurich
Universite Libre De Bruxelles
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 University Of Zurich, Universite Libre De Bruxelles filed Critical University Of Zurich
Priority to AU2001265714A priority Critical patent/AU2001265714A1/en
Publication of WO2001096878A2 publication Critical patent/WO2001096878A2/fr
Publication of WO2001096878A3 publication Critical patent/WO2001096878A3/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4727—Calcium binding proteins, e.g. calmodulin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders

Definitions

  • the present invention is related to a specific marker of neurodegenerative diseases, and its use for the screening of drugs used in the treatment and/or the prevention of said neurodegenerative diseases or dementia disorders.
  • Alzheimer's disease is a degenerative brain disorder characterised clinically by progressive loss of memory, reasoning, judgment and emotional stability that gradually leads to a deep mental deterioration and ultimately death.
  • ALS amyotrophic lateral sclerosis
  • Amyotrophic lateral sclerosis is a partly hereditary disease having an important incidence upon the population (between 1/10 000 and 1/20 000 affected patients in developed countries) .
  • astrocytes interact intimately with degenerating motor neurones in a mouse model of amyotrophic lateral sclerosis (Glia, Vol. 28, p. 215-224, 1999), which is now identified as astroglial reaction.
  • a prominent mouse model of the disease is represented by the transgenic mouse model SOD1 G93A, which carries, in addition to its wild type genome, an extra-copy of the mutant human gene SOD1 G93A (mutated human enzyme superoxide dismutase) .
  • the present invention is related to a new specific use of the known molecule, calcium-binding protein S100A6, also called calcyclin, which is present in a restricted number of astrocytes of the white matter (Pedrocchi et al . , Biochemistry, Vol. 33, P. 6732-6738, 1994) .
  • S100A6 immunoreactive astrocytes were mainly distributed in the outer part of the white matter (Yamashita N. et al . , J. Composition. Neurol . , Vol. 404, p. 235-257, 1999).
  • the inventors have discovered unexpectedly that said protein is a powerful marker associated with various neurodegenerative diseases and is a useful target for drug screening targeted against said neurodegenerative diseases or disorders.
  • the present* invention is related to a diagnostic and/or quantification (monitoring) kit comprising :
  • an antigenic structure consisting or comprising the calcium-binding protein S100A6 or an active portion thereof (epitope) , and/or
  • said antigenic structure could be an epitope of the calcium-binding protein S100A6 against which it is possible to raise a specific directed molecule, such as an antibody or an active portion thereof; said calcium-binding protein or epitope of said calcium-binding protein being possibly bonded to a suitable carrier molecule in order to improve the detection and/or the quantification of said protein (or molecule directed against said protein) in said patient, preferably upon an extra-corporal biological sample obtained from said patient.
  • the presence of said antigenic structure or said antibody in a human patient is preferably diagnosticed and/or quantified upon a tissue or extra-corporal biological sample obtained from said patient, such as cephalo-rachidian liquid, blood, serum, urine, lymph, ...
  • tissue or extra-corporal biological sample obtained from said patient, such as cephalo-rachidian liquid, blood, serum, urine, lymph, ...
  • detection upon an extra-corporal biological sample from a human is performed by detection methods well-known by the person skilled in the art, especially according to the quantitative serum assay described by KIEWITZ et al . (Biochem-Biophys . , Vol . 274, p. 865-871, 2000) .
  • the detection and/or the quantification can be based upon the expression or the over-expression of the antigenic structure according to the invention, the detection and/or the quantification of its binding to its corresponding receptor, or the detection and/or the quantification of the genetic sequence encoding said antigenic structure or an active portion thereof (mRNA or genomic DNA) .
  • the kit according to the present invention may also comprise a complementary genetic sequence of a genomic or mRNA genetic sequence encoding the antigenic structure according to the invention.
  • the detection method and means of the diagnostic kit are suitable for the detection upon said patient sample by immunohistochemistry, hybridisation or recognition by marked antibodies, especially ELISA (Enzyme Linked Immunosorbent Assay) or RIA (Radio Immunoassay) , on filter, on a solid support, in solution, in "sandwich", on gel, Dot blot hybridisation, Western blot, Northern blot hybridisation, Southern blot hybridisation, isotopic or non-isotopic labelling (such as immunofluorescence or biotinylation) , cold probes technique, genetic amplification, particularly PCR or LCR, double immunodiffusion, capillary and counter- immunoelectrophoresis, haemagglutination and/or a combination thereof.
  • ELISA Enzyme Linked Immunosorbent Assay
  • RIA Radio Immunoassay
  • Another aspect of the present invention is related to the use of the marker according to the invention (or any molecule directed against it) for a drug screening of compounds targeted against said neurodegenerative diseases and syndromes, especially for a drug screening of compounds which could be used as inhibitors (antagonists) of said antigenic structure to its receptor.
  • a further aspect of the present invention is therefore related to the use of said drugs, especially said compounds in the prevention and/or the treatment of various neurodegenerative diseases or syndromes, including associated diseases.
  • neurodegenerative diseases or disorders the preferred diseases selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huttington' s disease, stroke, multi-sclerosis and amyotrophic lateral sclerosis.
  • the Fig. 1 shows the S100A6 immunohistochemistry mice brainstem of a normal mouse and a SOD1 mutated mouse (several views of the same histological sample are presented)
  • the Fig. 2 represents an analysis of histological brain sample obtained from a patient, having suffered from amyotrophic lateral sclerosis.
  • SOD1 G93A superoxide dismutase
  • 'SOD1 transgenic mice develop severe damages of motor neurones at an age of several months and constitute a valuable animal model for the human neurodegenerative disease amyotrophic lateral sclerosis.
  • Obvious signs of the disease are disorders of motor function in one or more limbs leading to paralysis of the motoric system.
  • the transgenic SOD1 G93A mice develop normally for 6-8 months, but were sacrified for an immunohistochemical analysis of their calcium-binding proteins when signs of the disease could be detected.
  • Brain and spinal cord from normal and mutant mice were dissected and fixed Metacarn or perfusion with PAF 4%. Paraffin sections were used for S100A6 immunohistochemistry. Results show a dramatic increase in the number of positive S100A6 astrocytes located in the brainstem, in particular in the ventral medullar reticular nucleus (MDRV) , the root of the hypoglossal nerve (12n) , in white matter and in ventral horn of the spinal cord.
  • MDRV ventral medullar reticular nucleus
  • 12n the root of the hypoglossal nerve
  • This increase in the S100A6 may alter Ca 2+ and Zn 2+ homeostasis in both astrocytes and motor neurones of the brainstem and spinal cord and thus may reflect cellular reorganisations associated with the pathogenesis of the disease.
  • Another aspect of the present invention is related to the use of said drugs or inhibitors in the prevention and/or the treatment of amyotrophic lateral sclerosis and/or the associated diseases, especially the associated immune diseases and cancers .
  • the marker can be advantageously used in the kit and method according to the invention for detecting early stages of the disease.
  • a specific aspect of the present invention is related to the new antibody raised in goat (litres of high titre antibody) which are highly specific against the recombinant human calcium binding protein according to the invention (marker or antigenic structure according to the invention) , which is preferably obtained according to the method described in the example 1 and which is highly specific as shown by the inventors by using the method of Ilg et al . (Int. J. cancer, Vol. 68, p.
  • Such polyclonal antibody is specially suitable for the preparation of an ELISA test which can be used for the detection, the quantification and the monitoring of the expression of the antigenic structure according to the invention in a patient.
  • the monitoring of the level S100A6 protein can be performed after drug prescription, especially if such new drug shows beneficial effects upon the patient.
  • the use of the specific antibody according to the invention permits a significant speed up in the testing of new neuroprotective drugs tested upon the mouse model of amyotrophic lateral sclerosis.
  • the inventors have also identified upon tissue samples from patients having suffered from Alzheimer's disease an important S100A6 distribution.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Analytical Chemistry (AREA)
  • Psychiatry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hospice & Palliative Care (AREA)
  • Food Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une trousse de diagnostic pour la détection et/ou la quantification d'une maladie ou d'une pathologie neurodégénérative. Cette trousse comprend une structure antigénique renfermant la protéine de liaison au calcium S100A6 (calcycline) ou une partie active (épitope) de ladite protéine, une molécule dirigée contre cette structure antigénique (ou contre une partie active de cette structure) et/ou une séquence nucléotidique capable de s'hybrider avec la séquence nucléotidique codant pour ladite protéine.
PCT/BE2001/000100 2000-06-14 2001-06-14 Marqueur pour maladies neurodegeneratives et son utilisation pour le criblage de medicaments diriges contre lesdites maladies WO2001096878A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001265714A AU2001265714A1 (en) 2000-06-14 2001-06-14 Marker for neurodegenerative diseases and its use for drug screening targeted against said diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21141200P 2000-06-14 2000-06-14
US60/211,412 2000-06-14

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WO2001096878A2 true WO2001096878A2 (fr) 2001-12-20
WO2001096878A3 WO2001096878A3 (fr) 2002-06-13

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AU (1) AU2001265714A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009109862A2 (fr) * 2008-03-06 2009-09-11 Rolf Lewensohn Substances thérapeutiques anticancéreuses améliorées
US20140057307A1 (en) * 2010-08-10 2014-02-27 Bioftalmik S.L. Method for the diagnosis of dry eye and blepharitis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001471A1 (fr) * 1996-07-05 1998-01-15 Ab Sangtec Medical Methodes pour determiner la presence de la proteine cerebrale s-100
WO1998037420A1 (fr) * 1997-02-24 1998-08-27 Markus Otto Procede pour diagnostiquer l'encephalopathie spongiforme transmissible

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001471A1 (fr) * 1996-07-05 1998-01-15 Ab Sangtec Medical Methodes pour determiner la presence de la proteine cerebrale s-100
WO1998037420A1 (fr) * 1997-02-24 1998-08-27 Markus Otto Procede pour diagnostiquer l'encephalopathie spongiforme transmissible

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HEIZMANN CLAUS W ET AL: "New perspectives on S100 proteins: A multi-functional Ca2+-, Zn2+- and Cu2+-binding protein family." BIOMETALS, vol. 11, no. 4, December 1998 (1998-12), pages 383-397, XP008001661 ISSN: 0966-0844 *
HEIZMANN CLAUS W: "Ca2+-binding S100 proteins in the central nervous system." NEUROCHEMICAL RESEARCH, vol. 24, no. 9, 1999, pages 1097-1100, XP008001662 ISSN: 0364-3190 *
HOYAUX DAPHNE ET AL: "S100 proteins in Corpora amylacea from normal human brain." BRAIN RESEARCH, vol. 867, no. 1-2, 2000, pages 280-288, XP002194140 ISSN: 0006-8993 *
PERSSON L ET AL: "S-100 PROTEIN AND NEURON-SPECIFIC ENOLASE IN CEREBROSPINAL FLUID AND SERUM MARKERS OF CELL DAMAGE IN HUMAN CENTRAL NERVOUS SYSTEM" STROKE, vol. 18, no. 5, 1987, pages 911-918, XP000913410 ISSN: 0039-2499 *
TONINI G P ET AL: "Gene expression and protein localisation of calcyclin, a calcium-binding protein of the S-100 family in fresh neuroblastomas." EUROPEAN JOURNAL OF CANCER, vol. 31A, no. 4, 1995, pages 499-504, XP002194141 ISSN: 0959-8049 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009109862A2 (fr) * 2008-03-06 2009-09-11 Rolf Lewensohn Substances thérapeutiques anticancéreuses améliorées
WO2009109862A3 (fr) * 2008-03-06 2009-12-03 Rolf Lewensohn Substances thérapeutiques anticancéreuses améliorées
US20140057307A1 (en) * 2010-08-10 2014-02-27 Bioftalmik S.L. Method for the diagnosis of dry eye and blepharitis

Also Published As

Publication number Publication date
AU2001265714A1 (en) 2001-12-24
WO2001096878A3 (fr) 2002-06-13

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