WO2010084150A1 - Procédé de diagnostic pour détecter des maladies neurodégénératives - Google Patents

Procédé de diagnostic pour détecter des maladies neurodégénératives Download PDF

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Publication number
WO2010084150A1
WO2010084150A1 PCT/EP2010/050681 EP2010050681W WO2010084150A1 WO 2010084150 A1 WO2010084150 A1 WO 2010084150A1 EP 2010050681 W EP2010050681 W EP 2010050681W WO 2010084150 A1 WO2010084150 A1 WO 2010084150A1
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WO
WIPO (PCT)
Prior art keywords
nrg
isoform
neuregulin
sample
neurodegenerative diseases
Prior art date
Application number
PCT/EP2010/050681
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English (en)
Inventor
André SCHRATTENHOLZ
Original Assignee
Proteosys Ag
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 Proteosys Ag filed Critical Proteosys Ag
Publication of WO2010084150A1 publication Critical patent/WO2010084150A1/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
    • 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
    • G01N2333/475—Assays involving growth factors
    • G01N2333/4756—Neuregulins, i.e. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
    • 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 invention relates to a method for the diagnosis of neurodegenerative diseases in a sample by determining the presence and/or amount of an acidic isoform of neuregulin-1 ⁇ > (NRG-Ki) in body fluids.
  • Neuregulins also ARIA, neurogenic differentiation factors, heregulins and DDF
  • ARIA neurogenic differentiation factors
  • DDF neurogenic differentiation factors
  • NRG-1, NRG-2, NRG-3 and NRG-4 Due to alternative splicing and posttranslational modification like proteolytic cleavage, phosphorylation and glycosylation the NRG-family members encode many different soluble and transmembrane isoforms. They have been shown to play important roles e.g. in the development of the nervous system. For example in publication Ozaka M.
  • WO 99/18976 describes a method for the treatment and/or prophylaxis of neurological diseases comprising administering a neuregulin, or a fragment or derivative of a neuregulin, or a nucleic acid coding for a neuregulin or a neuregulin fragment or derivative thereof to a patient.
  • WO 99/18976 only tests on gene level are performed. Since up to over 100 different molecular protein species can be generated from one single gene by modifications on transcript or/and protein level, the indications in WO 99/18976 are not sufficient to identify the protein species actually relevant to neurological processes.
  • WO 98/55611 describes the use of a 15 bp-long neuregulin-response- element in therapeutical processes and screening methods for the identification of active agents.
  • PCT/EP01/01424 discloses an acidic neuregulin- ⁇ isoform having an isoelectric point of ⁇ pH 7, particularly from pH 4.3 to pH 5.0 and more particularly from pH 4.5 to pH 4.7. This neuregulin- ⁇ isoform was found in mammalian hippocampal cells and characterized as indicator or target, respectively, for neuronal processes.
  • PCT/EP02/08778 discloses further neuregulin- ⁇ isoforms associated with neuronal processes and the use of these isoforms as a target for modulating memory and learning in a mammal.
  • NRG-1 ⁇ isoform is transported from mammalian central nervous tissues, e.g. brain into body fluids, e.g. into the CSF in neurodegenerative disorders. Furthermore this isoform might be transported via the blood-brain-barrier into the periphery of the body.
  • a subject-matter of the present invention is a method for diagnosing and/or monitoring a neurodegenerative disease or condition like e.g. Alzheimer's disease, Parkinson's disease and stroke-related conditions, comprising determining the presence and/or amount of a NRG-1 ⁇ isoform in a body fluid sample.
  • An increased amount of a NRG-1fi> isoform versus a control e.g. a sample derived from a normal/healthy subject may be an indication of a neurodegenerative disease or the susceptiblity of the subject for such a condition.
  • the NRG-1 ⁇ isoform preferably has an acidic isoelectric point of about ⁇ pH 7, e.g. of about pH 4 to pH 5. Further the isoform preferably has an apparent molecular weight (SDS-PAGE) of about 25-35 kD, e.g. of about 30-32 kD. This isoform preferably comprises the extracellular domain of human NRG-1 ⁇ .
  • the sample may be a mammalian, e.g. human body fluid sample, particularly neuronal fluid, more particularly liquor (cerebrospinal fluid). Further the sample may also be obtained from peripheral body fluids, particularly blood, plasma or serum.
  • the diagnostic method preferably comprises detection of the NRG-1 ⁇ isoform by immunological methods, e.g. using anti-neuregulin- ⁇ antibodies. Such methods are well known in the art.
  • the method comprises determining molecular weight and/or isoelectric point of this isoform. Therefore, an NRG-1 ⁇ isoform containing sample may be subjected to a procedure, wherein proteins are seperated according to their molecular weight and/or charge.
  • the separation procedure may be e.g. gel electrophoresis such as SDS-PAGE or an equivalent method.
  • determination may comprise chromatographic separation procedures such as HPLC and/or molecular weight exclusion chromatography.
  • a quantitative or semiquantitative determination of a NRG-1 ⁇ isoform e.g. of a single NRG-1 ⁇ isoform as described above is carried out.
  • This quantitative or semi- quantitative determination may comprise the use of labelled detection reagents such as neuregulin- ⁇ antibodies and quantitatively or semi- quantitatively determining the amount of label bound to a respective neuregulin- ⁇ form in a sample.
  • the method additionally comprises a determination of an internal standard, e.g. a reference protein, which allows quantification of the neuregulin- ⁇ isoform to be determined.
  • the reference protein exhibits characteristics, e.g.
  • the reference protein may be selected from biological extracts, which contain predetermined amounts of recombinant or native neuregulin- ⁇ , purified or partially purified native neuregulin- ⁇ proteins from biologic material, e.g. 42 kD protein from rat hippocampus cell line HK3, purified recombinant protein, e.g. full-length or truncated neuregulin- ⁇ protein or hybrid protein conatining relevant neuregulin- ⁇ epitopes as a ,,tag" coupled to a suitable carrier.
  • biological extracts which contain predetermined amounts of recombinant or native neuregulin- ⁇ , purified or partially purified native neuregulin- ⁇ proteins from biologic material, e.g. 42 kD protein from rat hippocampus cell line HK3, purified recombinant protein, e.g. full-length or truncated neuregulin- ⁇ protein or hybrid protein conatining relevant neuregulin- ⁇ epitopes as a ,,tag
  • the method of the invention may comprise a diagnostic procedure, wherein a subject to be tested, e.g. a subject presumed to be suffering from or to be susceptible for a neurodegenerative disease is tested.
  • the method of the invention may involve the monitoring of the course of a neurodegenerative disease in a subject, particularly a therapy control.
  • the invention relates to the use of a reagent kit, comprising detection reagents for NRG-1 ⁇ , e.g. anti-NRG-1 ⁇ antibodies for the diagnosis of neurodegenerative diseases and conditions, particularly in a method as described above. Further, the present invention shall be explained in more detail by the following Figure and Example.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur un procédé pour le diagnostic de maladies neurodégénératives dans un échantillon par la détermination de la présence et/ou de la quantité d'un isoforme acide de la neuregulin-1β (NRG-1β) dans des fluides corporels.
PCT/EP2010/050681 2009-01-23 2010-01-21 Procédé de diagnostic pour détecter des maladies neurodégénératives WO2010084150A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14675209P 2009-01-23 2009-01-23
US61/146,752 2009-01-23

Publications (1)

Publication Number Publication Date
WO2010084150A1 true WO2010084150A1 (fr) 2010-07-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/050681 WO2010084150A1 (fr) 2009-01-23 2010-01-21 Procédé de diagnostic pour détecter des maladies neurodégénératives

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055611A1 (fr) 1997-06-06 1998-12-10 Regents Of The University Of Michigan Element de reponse a la neureguline et ses utilisations
WO1999018976A1 (fr) 1997-10-14 1999-04-22 Cambridge Neuroscience, Inc. Methode therapeutiques comportant l'utilisation d'une neureguline
WO2003014156A2 (fr) * 2001-08-06 2003-02-20 Proteosys Ag Isoformes de neureguline-$g(b) associes a des processus neuronaux
WO2004019045A2 (fr) * 2002-08-23 2004-03-04 Proteosys Ag Procede de diagnostic de la maladie d'alzheimer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055611A1 (fr) 1997-06-06 1998-12-10 Regents Of The University Of Michigan Element de reponse a la neureguline et ses utilisations
WO1999018976A1 (fr) 1997-10-14 1999-04-22 Cambridge Neuroscience, Inc. Methode therapeutiques comportant l'utilisation d'une neureguline
WO2003014156A2 (fr) * 2001-08-06 2003-02-20 Proteosys Ag Isoformes de neureguline-$g(b) associes a des processus neuronaux
WO2004019045A2 (fr) * 2002-08-23 2004-03-04 Proteosys Ag Procede de diagnostic de la maladie d'alzheimer

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FALLS D L: "Neuregulins: Functions, forms, and signaling strategies.", EXP CELL RES, vol. 284, no. 1, 10 March 2003 (2003-03-10), pages 14 - 30, XP002573567 *
KASTIN ET AL., J NEUROCHEM, vol. 88, no. 4, 2004, pages 965 - 970
OZAKA M. ET AL., NATURE, vol. 390, no. 6661, 10 December 1997 (1997-12-10), pages 691 - 4
PANKONIN M S ET AL: "Differential distribution of neuregulin in human brain and spinal fluid.", BRAIN RES, vol. 1258, 29 December 2008 (2008-12-29), pages 1 - 11, XP002573566 *
SCHILLO ET AL., J PROTEOM RES, vol. 4, 2005, pages 900 - 908

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