WO2001096878A2 - Marker for neurodegerative diseases and its use in drug screening - Google Patents
Marker for neurodegerative diseases and its use in drug screening Download PDFInfo
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- 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
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- disease
- neurodegenerative disease
- disorder
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- protein
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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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Abstract
The present invention is related to a diagnostic kit for the detection and/or quantification of a neurodegenerative disease or pathology, comprising an antigenic structure consisting of the calcium-binding protein S100A6 (calcyclin) or comprising an active portion (epitope) thereof, a molecule directed against said antigenic structure (or an active portion thereof) and/or a nucleotide sequence able to hybridise with the nucleotide sequence encoding said protein.
Description
MARKER FOR NEURODEGENERATIVE DISEASES AND ITS USE FOR DRUG SCREENING TARGETED AGAINST SAID DISEASES
Field of the invention
[0001] 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.
Background of the invention and state of the art [0002] The appearance of neurodegenerative diseases and dementia disorders, in particular disorders caused by regressive cellular changes becomes more likely with increased age.
[0003] Manifestation of aeging in connection with the central nervous system may be accompanied by multiple structural and functional alterations. [0004] These include cerebral shrinkage and loss of brain weight, nerve cell degeneration and lesion of the cerebral vessel connective tissues .
[0005] However, it exists also neurodegenerative diseases which affect also the younger population and which are not already correlated with dementia disorders.
[0006] Among the neurodegenerative diseases, one may cite Alzheimer's disease, which 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.
[0007] Other pathologies or diseases which fall under the definition of neurodegenerative diseases are stroke (and other diseases affecting the brain having a possible ischemic origin), Parkinson's disease, Huttington' s disease, multiple sclerosis and amyotrophic lateral sclerosis . [0008] Among said diseases, amyotrophic lateral sclerosis (ALS) is a mortal disease affecting motor neurones for which no efficient drug exists.
[0009] 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) .
[0010] Some authors state that 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.
[0011] 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) .
[0012] Both in human forms and corresponding transgenic mouse models of the disease, the presence of this mutated gene leads to a selective degeneration of defined motor neurone population in the spinal cord, brain stem and motor cortex by a calcium-dependent , "excitotoxic" mechanism.
[0013] According to the present models, degeneration of motor neurones is primarily mediated by a toxic "gain of function" of mutant SOD1, where "aggregates" of mutant SOD1
are thought to inhibit glutamate transport, thus leading to over-excitation of glutamatergic synapses, subsequent overloading of vulnerable motor neurones with excess calcium and activation of apoptotic mechanisms. [0014] Early detection of the disease is currently under investigation.
[0015] An antibody against SOD1 has been already described in the literature (Pardo et al . , P.N.A.S., USA, Vol. 92(4), p. 954-958, 1995; Bruj in et al . , Science 281, p.1851-1854, 1998 and Cleveland, Neuron, Vol. 24(3), p. 515-520, 1999) .
Summary of the invention [0016] 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) . [0017] In the rat spinal cord, 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). [0018] 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.
[0019] The inventors have discovered that said antigenic structure (apo or Ca loaded form of S100A6) possibly bonded to a carrier molecule (BSA, hemocyanine, solid supports such as beads, filters, etc.) and active portions thereof (especially epitopes) can raise antibodies or active portions of said antibodies (such as
hypervariable (FAB, FAB2 ' , etc) portions of an antibody directed specifically against said antigenic structure) . [0020] Therefore, 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
• possibly a molecule directed against said antigenic structure, such as an antibody or active portion (s) thereof,
• possibly the receptor of said protein S100A6, and
• all the media and means for the detection and/or the quantification of said antigenic structure or any molecule directed against it, in a patient (especially in a human patient) .
[0021] According to the invention, 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.
[0022] 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, ...
[0023] Preferably, such 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) .
[0024] 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) . [0025] Therefore, 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. [0026] Preferably, 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.
[0027] 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.
[0028] 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.
[0029] According to the invention it is meant by 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.
[0030] The present invention will be described in details in the following example in reference to the enclosed figures .
Short description of the Figures
[0031] 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) [0032] The Fig. 2 represents an analysis of histological brain sample obtained from a patient, having suffered from amyotrophic lateral sclerosis.
Detailed description of the invention [0033] The inventors have compared the S100A6 distribution in the brainstem and spinal cord from normal and transgenic mice carrying a extra-gene encoding the mutated human enzyme superoxide dismutase (SOD1 G93A) (Gurney et al . , Science, Vol. 264, p. 1772-1775, 1994).
[0034] '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. [0035] Obvious signs of the disease are disorders of motor function in one or more limbs leading to paralysis of the motoric system.
[0036] 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. [0037] In addition, large cells located in the grey matter were intensively S100A6 immunoreactive, as shown in the enclosed figure 1.
[0038] This increase in the S100A6 may alter Ca2+ and Zn2+ 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.
[0039] Similar experiments made upon brain histologic samples of humans affected with a neurodegenerative disease amyotrophic lateral sclerosis shown also that the detection of the calcium-binding protein could be associated with the detection and the development of amyotrophic lateral sclerosis .
[0040] 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 .
[0041] The marker can be advantageously used in the kit and method according to the invention for detecting early stages of the disease. [0042] Advantageously, 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.
325-332, 1996) .
[0043] 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.
[0044] The monitoring of the level S100A6 protein can be performed after drug prescription, especially if such new drug shows beneficial effects upon the patient. [0045] Furthermore, 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.
[0046] Indeed, while previous studies had to wait for the death of patients initiated by motor neurones degeneration, it is now possible to use the marker and antibody according to the invention to monitor the
progression of the disease without having to wait for patient death.
[0047] The inventors have also identified upon tissue samples from patients having suffered from Alzheimer's disease an important S100A6 distribution.
Claims
1. Diagnostic kit for the detection and/or the quantification of a neurodegenerative disease or pathology, comprising an antigenic structure consisting of
5 the calcium-binding protein S100A6 (calcyclin) or comprising an active portion (epitope) thereof, a molecule directed against said antigenic structure (or an active portion thereof) and/or a nucleotide sequence able to hybridise with the nucleotide sequence encoding said 10 protein.
2. The diagnostic kit according to Claim 1, comprising the media for the detection and/or the quantification of said antigenic structure, said molecule or said sequence in an extra-corporal biological sample
15 obtained from a patient, preferably by a method selected from the group consisting of immunohistochemistry, hybridisation or recognition by marked antibodies, especially ELISA or RIA, hybridisation on filters, on solid supports, in solution, in "sandwich", on gel, Dot blot 0. hybridisation, Western blot, Northern blot hybridisation, Southern blot hybridisation, isotopic or non-isotopic labelling, cold probes technique, genetic amplification, double immunodiffusion, capillary or counter- immunoelectrophoresis, haemagglutination or a combination
25 thereof.
3. The diagnostic kit according to any of the preceding claims 1 or 2 , for the detection and/or the quantification of a neurodegenerative disease or pathology selected from the group consisting of Alzheimer's disease,
30 Huttington' s disease, Parkinson's disease, stroke, multiple sclerosis and amyotrophic lateral sclerosis, in a patient, preferably a human patient .
4. A method for the screening of active pharmaceutical compounds used for the treatment and/or the prevention of a neurodegenerative disease or disorder comprising the steps of :
• identifying any compound able to bind to the calcium-binding protein S100A6 or the nucleotide sequence encoding said protein,
• possibly testing said compound upon animal models of said neurodegenerative disease or disorder, and
• recovering said compound directed against said calcium- binding protein S100A6 or the nucleotide sequence encoding said protein.
5. Unknown compound identified and recovered by the method according to the Claim 4.
6. Pharmaceutical composition comprising an adequate amount of unknown compound according to the Claim 5 and an adequate pharmaceutical carrier.
7. Method of treatment and/or prevention of a neurodegenerative disease or disorder in a mammal patient, preferably a human patient, suffering from said disease and comprising the step of administrating a sufficient amount of the pharmaceutical composition according to the Claim 6 for preventing and/or treating the symptoms of said disease or disorder.
8. Use of the pharmaceutical composition according to the Claim 6, for the manufacture of a medicament in the treatment and/or the prevention of a neurodegenerative disease or disorder.
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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2001096878A2 true WO2001096878A2 (en) | 2001-12-20 |
| WO2001096878A3 WO2001096878A3 (en) | 2002-06-13 |
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ID=22786822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BE2001/000100 WO2001096878A2 (en) | 2000-06-14 | 2001-06-14 | Marker for neurodegerative diseases and its use in drug screening |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2001265714A1 (en) |
| WO (1) | WO2001096878A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009109862A3 (en) * | 2008-03-06 | 2009-12-03 | Rolf Lewensohn | S100a6 and/or s100a4 inhibitors for treating cancer |
| US20140057307A1 (en) * | 2010-08-10 | 2014-02-27 | Bioftalmik S.L. | Method for the diagnosis of dry eye and blepharitis |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9602677D0 (en) * | 1996-07-05 | 1996-07-05 | Sangtec Medical Ab | Methods for determining brain antigens |
| DE19707230C2 (en) * | 1997-02-24 | 2000-01-13 | Markus Otto | Method for recognizing a disease of an organism from transmissible spongiform encephalopathy |
-
2001
- 2001-06-14 AU AU2001265714A patent/AU2001265714A1/en not_active Abandoned
- 2001-06-14 WO PCT/BE2001/000100 patent/WO2001096878A2/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009109862A3 (en) * | 2008-03-06 | 2009-12-03 | Rolf Lewensohn | S100a6 and/or s100a4 inhibitors for treating cancer |
| 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 (en) | 2002-06-13 |
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