Method for detecting a progressive, chronic dementia disease, and corresponding peptides and detection reagents

Abstract

Novel peptides and the quantitative methods for the determination thereof in body fluids of patients suffering from progredient chronic dementia, in relation to the concentration of said peptides in a control group. The peptides derive from a protein precursor having the corresponding gene, are processed in a specific manner, and are optionally post-translationally modified, especially phosphorylised. An increase in the concentrations of these peptides or the corresponding non-processed protein indicates progredient chronic dementia. Also disclosed are methods of using the peptides for controlling the course of progredient chronic dementia and for the prognosis of progredient chronic dementia, especially for complementing or replacing mini-mental scores, and for developing therapeutic agents to combat progredient chronic dementia such as Alzheimer's disease.

1 . A method for detecting a progressive, chronic dementia disease or a predisposition to such a disease by identifying at least one marker peptide in a biological sample from an individual, where the marker peptide is a peptide which is derived from the sequence having the Gene Bank accession No. X13694 or a sequence homologous thereto.  
     
     
         2 . (canceled)  
     
     
         3 . The method as claimed in  claim 1 , characterized in that the peptide 
 a) is a DROPN peptide,    b) is a peptide corresponding to accession No. X13694, or    c) is a derivative of a naturally occurring everything of the peptides mentioned under a) or b), or    d) is a DROPN mutant, where the DROPN mutant preferably differs in a maximum of 2, amino acids from the corresponding unmutated DROPN sequence, or    e) is a mutant of one of the peptides mentioned under b) or c), where the amino acid sequence differs by a maximum of 30% from the amino acid sequence mentioned under b) or c), or    f) is a chemically modified, or post-translationally modified peptide corresponding to a) to e).    
     
     
         4 . (canceled)  
     
     
         5 . The method as claimed in any of claims  1 , characterized in that the progressive, chronic dementia disease is Alzheimer's disease or a related neurological disease, in particular Lewy body dementia or vascular dementia.  
     
     
         6 . (canceled)  
     
     
         7 . The method as claimed in any of claims  1 , characterized in that for a positive detection of the disease the peptide concentration is increased or reduced for each of the peptides in a specific direction relative to the concentration of the respective peptide in a control sample.  
     
     
         8 . The method as claimed in any of claims  1 , characterized in that it is used to determine the severity of the disease, in particular as substitute or supplement carrying out a mini-mental state examination (MMSE), or to diagnose preliminary stages of neurological diseases, in particular mild cognitive impairment (MCI), or for prognosis of the course of the disease.  
     
     
         9 .- 12 . (canceled)  
     
     
         13 . The method as claimed in  claim 1 , characterized in that the peptides are identified with the aid of an immunological test, wherein the immunological test is an ELISA (enzyme linked immuno sorbent assay), a radioimmunoassay or a Western blot.  
     
     
         14 . The method as claimed in  claim 1 , characterized in that the identification of the peptide(s) is carried out with the aid of an antibody directed to a peptide used according to the invention, of an antibody fragment, of a phage particle, or of PNAs or of an affinity matrix.  
     
     
         15 .- 16 . (canceled)  
     
     
         17 . A peptide that 
 a) is a DROPN peptide,    b) is a DROPN derivative of a naturally occurring OPN protein, in particular a derivative of X13694, or    c) is a DROPN derivative of an OPN allele, or    d) is a DROPN mutant, where the DROPN mutant preferably differs in a maximum of 2, amino acids from the corresponding unmutated DROPN sequence, or    e) is a chemically, or post-translationally modified peptide corresponding to a) to d).    
     
     
         18 . The use of at least one of the DROPN peptides as claimed in  claim 17  for obtaining antibodies and/or for developing diagnostic reagents for the detection of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         19 . Antibodies which bind the DROPN peptides as claimed in  claim 17 .  
     
     
         20 . The use of the antibodies according to  claim 19  against osteopontin or for the diagnosis of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         21 . The use of nucleic acids which correspond to DROPN peptides or to OPN proteins for the indirect determination and/or quantification of the relevant proteins and peptides.  
     
     
         22 . The use of a method corresponding to  claim 21 , in which the detection of the OPN nucleic acids takes place by using Northern blots, reverse transcriptase PCR or quantitative PCR.  
     
     
         23 . A method for determining the efficacy of a therapy for a neurological disease, in particular for a progressive, chronic dementia disease, in particular for Alzheimer's disease.  
     
     
         24 . The method as claimed in  claim 23  further comprising the step of stratifying patients who are suitable for therapies or clinical studies of neurological diseases, in particular chronic dementia diseases, in particular Alzheimer's disease.  
     
     
         25 . Nucleic acids which correspond to DROPN peptides.  
     
     
         26 . Nucleic acids which are suitable as OPN-specific antisense nucleic acids or as OPN-specific ribozymes, or as OPN-specific triplex nucleic acids.  
     
     
         27 . Agonists or antagonists of the OPN peptides according to  claim 17 .  
     
     
         28 . Peptides according to  claim 1  wherein these peptides are pharmaceutically processed or chemically or biologically modified in such a way that they are able to cross the blood-brain barrier and/or the blood-CSF barrier.  
     
     
         29 . Peptides according to  claim 1 , wherein these peptides are pharmaceutically processed or chemically or biologically modified in such a way that they are optimized for specific administration routes, in particular for administration into the bloodstream, the gastrointestinal tract, the urogenital tract, the lymphatic system, into the subarachnoid space, for inhalation or for direct injection into tissue such as, for example, muscle tissue, adipose tissue, brain etc.  
     
     
         30 . The peptides according to  claim 1  for use as a medicament or medicament active ingredient.  
     
     
         31 . The peptides according to  claim 1  for use in the production of a medicament for the prophylaxis or treatment of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         32 . The use of at least one substance which modulates the expression of OPN proteins, for the production of a medicament for the prophylaxis or treatment of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         33 . The use of a substance which binds to at least one of the peptides used in  claim 1  to  16 , in particular of antibodies, antibody fragments, PNAs or affinity matrices for the production of a medicament for the prophylaxis or treatment of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         34 . The peptides according to  claim 1  for use in the therapy of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         35 . A method for therapeutically modulating the concentration of a DROPN peptide in a patient with a neurological disease, in particular chronic dementia diseases,—in particular Alzheimer's disease.  
     
     
         36 . The method according to  claim 35 , in which a reduction in the concentrations of OPN peptides, DROPN-peptides or OPN nucleic acids is desired.  
     
     
         37 . The method according to  claim 35 , in which an increase in the concentrations of OPN proteins, DROPN peptides or OPN nucleic acids is desired.  
     
     
         38 . The method according to  claim 36 , in which 
 a) antibodies directed against OPN proteins or DROPN peptides are administered,    b) antisense nucleic acids, triplex nucleic acids or ribozymes are administered, in order to reduce the expression of OPN proteins or DROPN peptides, or    c) substances which inhibit the processing of OPN proteins are administered, or    d) antagonists of the OPN peptides used in  claim 1  are administered to a patient.    
     
     
         39 . The method according to  claim 37 , in which 
 a) OPN proteins or DROPN peptides are administered, or    b) nucleic acids which code for OPN proteins or DROPN peptides are administered, or    c) substances which promote the processing of OPN proteins are administered, or    d) agonists of the OPN peptides used in  claim 1  are administered to a patient.    
     
     
         40 . A screening method for identifying substances able to reduce or enhance the expression of a DROPN peptide.  
     
     
         41 . A screening method according to  claim 40  for identifying receptors, or inhibitors which bind to said DROPN peptide.  
     
     
         42 . A screening method according to  claim 40  for identifying agonists or antagonists, of said DROPN peptide.  
     
     
         43 . (canceled)  
     
     
         44 . Nucleic acids according to  claim 25 , wherein thesenucleic acids are pharmaceutically processed or chemically or biologically modified in such a way that they are able to cross the blood-brain barrier and/or the blood-CSF barrier.  
     
     
         45 . The nucleic acids according to  claim 44  for use as a medicament or medicament active ingredient.  
     
     
         46 . The nucleic acids according to  claim 44  for use in the production of a medicament for the prophylaxis or treatment of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.  
     
     
         47 . The agonists or antagonists of the OPN peptides according to  claim 27 , wherein these nucleic acids are pharmaceutically processed or chemically or biologically modified in such a way that they are able to cross the blood-brain barrier and/or the blood-CSF barrier.  
     
     
         48 . The agonists or antagonists of the OPN peptides according to  claim 27  for use as a medicament or medicament active ingredient.  
     
     
         49 . The agonists or antagonists of the OPN peptides according to  claim 27  for use in the production of a medicament for the prophylaxis or treatment of neurological diseases, in particular of chronic dementia diseases, in particular of Alzheimer's disease.