Methods of treating psychosis and schizophrenia based on polymorphisms in the cntf gene

Abstract

This invention relates to the use of the association between the 103 G>A polymorphism in the CNTF gene to determine antipsychotic treatment strategies in patients with psychotic disorders.

1 . A method of treating a psychotic disorder in a patient in need of such treatment comprising: 
 (a) determining for the two copies of the CNTF gene present in the individual the identity of the nucleotide pair at the polymorphic site 103 G>A in GenBank sequence reference No. X55890 (Version 1) wherein;    (b) if both nucleotide pairs are G or if both are A then the individual is treated with lloperidone.    
     
     
         2 . The method of  claim 1  wherein if one nucleotide pairs is A and one is G then the individual is treated with alternative therapy or with lloperidone in combination with an alternative therapy.  
     
     
         3 . A method to treat a psychotic disorder in a patient in need of such treatment comprising: 
 (a) assaying for the presence of CNTF protein in the said patients body fluids or tissues;    (b) wherein, if CNTF protein is found in normal levels or is undetectable, the patient is treated with lloperidone, and    (c) if the CNTF protein is found in intermediate levels the patient is treated with alternative therapy or with lloperidone in combination with an alternative therapy.    
     
     
         4 . A method to treat a psychotic disorder in a patient in need of such treatment comprising: 
 (a) detecting a level of mRNA expression corresponding to the G variant of the CNTF gene at the polymorphic site 103 G>A in GenBank sequence reference No. X55890 (Version 1);    (b) detecting a level of mRNA expression corresponding to the A variant of the CNTF gene at the polymorphic site 103 G>A in GenBank sequence reference No. X55890 (Version 1);    (c) comparing the levels of mRNA detected in (a) and (b) above wherein, if (a) is two times or more the value of (b), or if (b) is two times or more the value of (a), the patient is treated with lloperidone (anti-psychotic medication), and if (a) and (b) are of similar value, the patient is treated with alternative therapy or with lloperidone in combination with an alternative therapy.    
     
     
         5 . A method to choose subjects for inclusion in a clinical study of an anti-psychotic medication comprising: 
 (a) determining for the two copies of the CNTF gene present in the individual, the identity of the nucleotide pair at the polymorphic site 103 G>A in GenBank sequence reference No. X55890 (Version 1) wherein,    (b) the individual is included in the study if both nucleotide pairs are G or both nucleotide pairs are A, and    (c) the individual is excluded from the study if one nucleotide pair is A and one is G.    
     
     
         6 . A kit for use in determining treatment strategy for a patient with a psychotic disorder comprising: 
 (a) an antibody able to recognize and bind to the polypeptide expression product of the CNTF gene;    (b) a container suitable for containing the said antibody and a sample of body fluid from the said individual wherein the antibody can contact the CNTF polypeptide if it is present, and    (c) means to detect the combination of the said antibody with CNTF polypeptide;    (d) instructions for use of kit.    
     
     
         7 . A kit for use in determining treatment strategy for a patient with a psychotic disorder comprising: 
 (a) a polynucleotide able to recognize and bind to the mRNA expression product of the CNTF gene;    (b) a container suitable for containing the said polynucleotide and a sample of body fluid from the said individual wherein the said polynucleotide can contact the CNTF mRNA, if it is present, and    (c) means to detect the combination of the said polynucleotide with the CNTF mRNA;    (d) instructions for use of kit.    
     
     
         8 . A kit for use in determining treatment strategy for a patient with a psychotic disorder comprising: 
 (a) a polynucleotide able to recognize and bind to some portion of the DNA sequence of the CNTF gene;    (b) a container suitable for containing the said polynucleotide and a sample of body fluid from the said individual wherein the polynucleotide can contact the CNTF DNA sequence If it is present, and    (c) means to detect the combination of the said polynucleotide with the CNTF DNA sequence;    (d) instructions for use of kit.    
     
     
         9 . A method for determining the responsiveness of an individual with a psychotic disorder to treatment with lloperidone, comprising; 
 (a) determining, for the two copies of the CNTF gene present in the individual, the identity of a nucleotide pair at a polymorphic site in the region of the CNTF gene that is in linkage disequilibrium with the polymorphic site at CNTF 103 G>A in GenBank sequence reference No. X55890 (Version 1); and    (b) assigning the individual to a good responder group if the nucleotide pair at a polymorphic site in the region of the CNTF gene that is in linkage disequilibrium with the polymorphic site at 103 G>A, indicates that, at the CNTF polymorphic site at 103 G>A, both nucleotide pairs are GC or both pairs are AT and to a low responder group if said nucleotide pair indicates that one pair is AT and one pair is GC at the CNTF 103 G>A site.    
     
     
         10 . A kit for the identification of a patient's polymorphism pattern at the CNTF polymorphic site at 103 G>A, said kit comprising a means for determining a genetic polymorphism pattern at the CNTF polymorphic site at 103 G>A.  
     
     
         11 . A kit according to  claim 10 , further comprising a DNA sample collecting means.  
     
     
         12 . A kit according to  claim 1 , wherein the means for determining a genetic polymorphism pattern at the CNTF polymorphic site at 103 G>A comprise at least one CNTF genotyping oligonucleotide.  
     
     
         13 . A kit according to claims  10 , wherein the means for determining a genetic polymorphism pattern at the CNTF polymorphic site at 103 G>A comprise two CNTF genotyping oligonucleotides.  
     
     
         14 . A kit according to any of claims  10 , wherein the means for determining a genetic polymorphism pattern at the CNTF polymorphic site at 103 G>A comprise at least one CNTF genotyping primer composition comprising at least one CNTF genotyping oligonucleotide.  
     
     
         15 . A kit according to  claim 14 , wherein the CNTF genotyping primer composition comprises at least two sets of allele specific primer pairs.  
     
     
         16 . A kit according to  claim 13 , wherein the two CNTF genotyping oligonucleotides are packaged in separate containers.  
     
     
         17 . A method according to  claim 1 , wherein the determination step (a) further comprises the use of a kit according to any  claims 10  to  16 .  
     
     
         18 . A kit for the identification of mRNA expression of the CNTF gene, said kit comprising a means for determining the mRNA product of the CNTF gene.  
     
     
         19 . A kit according to  claim 18 , wherein the means for determining the mRNA product of the CNTF gene comprises a polynucleotide capable of binding to the mRNA expression product of the CNTF gene.  
     
     
         20 . A kit according to  claim 18 , wherein the means for determining the mRNA product of the CNTF gene comprises at least one polynucleotide specific for one of the variants of the CNTF gene at the polymorphic site 103 G>A.  
     
     
         21 . A kit according to  claim 20 , wherein the polynucleotide is specific for mRNA expression of the G variant of the CNTF gene at the polymorphic site 103 G>A.  
     
     
         22 . A kit according to  claim 20 , wherein the polynucleotide is specific for mRNA expression of the A variant of the CNTF gene at the polymorphic site 103 G>A.  
     
     
         23 . A kit according to  claim 22 , wherein the polynucleotide is specific for the irregular mRNA coding for a truncated protein of 62 amino acids.  
     
     
         24 . A kit according to  claim 21 , wherein the polynucleotide is binding the mRNA expression product of the G or A variant of the CNTF gene under stringent hybridization conditions.  
     
     
         25 . A kit according to  claim 20 , wherein the means for determining the mRNA product of the CNTF gene comprise at least two polynucleotides, wherein one polynucleotide is specific for mRNA expression of the G variant of the CNTF gene at the polymorphic site 103 G>A, and the other polynucleotide is specific for mRNA expression of the A variant of the CNTF gene at the polymorphic site 103 G>A.  
     
     
         26 . A kit according to  claim 25 , wherein the two polynucleotides are packaged in separate containers.  
     
     
         27 . A method according to  claim 4 , wherein at least one of the determination steps (a) or (b) further comprises the use of a kit according to  claim 18 .  
     
     
         28 . A kit for the identification of a patient's CNTF protein level comprising a means for detecting the polypeptide expression product of the CNTF gene.  
     
     
         29 . A kit according to  claim 28 , wherein the means comprise an antibody recognizing the CNTF polypeptide.  
     
     
         30 . A kit according to  claim 29 , wherein the binding of the antibody is within a K D  range of 10e −6  to 10e −13 , preferable within a range of 10e −8  to 10e −12 .  
     
     
         31 . A method according to  claim 3 , wherein the assaying step (a) comprises the use of a kit.  
     
     
         32 . A kit according to  claim 10 , further comprising a means for collecting a body fluid or a tissue sample.  
     
     
         33 . A method according to  claim 1 , wherein said method is performed ex vivo.