Diagnostic and therapeutic compositions for alzheimer's disease

Abstract

The present invention relates to genetic mutations in mitochondrial cytochrome c oxidase genes that segregate with Alzheimer's disease (AD). The invention provides methods for detecting such mutations, as a diagnostic for Alzheimer's Disease, either before or after the onset of clinical symptoms. The invention further provides treatment of cytochrome c oxidase dysfunction.

We claim:  
     
         1 . A method for inhibiting the transcription or translation of mutant cytochrome c oxidase encoding genes, comprising the steps of: 
 a) contacting said genes with antisense sequences which are specific to said mutant sequences; and    b) allowing hybridization between said target mutant cytochrome c oxidase gene and said antisense sequences under conditions under which said antisense sequences bind to and inhibit transcription or translation of said target mutant cytochrome c oxidase genes without preventing transcription or translation of wild-type cytochrome c oxidase genes.    
     
     
         2 . The method of  claim 1  wherein Alzheimer's disease is treated and wherein said cytochrome c oxidase genes contain mutations at one or more codons selected from the group of: 
 (a) codon 155, codon 167, codon 178, codon 193, codon 194, and codon 415 of the cytochrome c oxidase I gene; and  
 (b) codon 20, codon 22, codon 68, codon 71, codon 74, codon 90, codon 95, codon 110, and codon 146 of the cytochrome c oxidase II gene.  
 
     
     
         3 . A probe for detection of a disease state associated with one or more mutations in mitochondrial cytochrome c oxidase genes comprising a nucleotide sequence complementary to either of the sense and anti-sense strands of said one or more mutations in said mitochondrial cytochrome c oxidase genes.  
     
     
         4 . The probe of  claim 3  wherein said probe includes a region complementary to the sense and anti-sense strands of one or more codons selected from the group of: 
 (a) codon 155, codon 167, codon 178, codon 193, codon 194, and codon 415 of the cytochrome c oxidase I gene; and  
 (b) codon 20, codon 22, codon 68, codon 71, codon 74, codon 90, codon 95, codon 110, and codon 146 of the cytochrome c oxidase II gene.  
 
     
     
         5 . A kit comprising a probe for detection of an Alzheimer's disease genotype, said probe comprising a nucleotide sequence complementary to either of the sense and anti-sense strands of a mitochondrial cytochrome c oxidase gene.  
     
     
         6 . The kit of  claim 5 , wherein said probe includes a region complementary to the sense and anti-sense strands of one or more codons selected from the group of: 
 (a) codon 155, codon 167, codon 178, codon 193, codon 194, and codon 415 of the cytochrome c oxidase I gene; and    (b) codon 20, codon 22, codon 68, codon 71, codon 74, codon 90, codon 95, codon 110, and codon 146 of the cytochrome c oxidase II gene.    
     
     
         7 . A therapeutic composition comprising antisense sequences which are specific to mutant cytochrome c oxidase genes or mutant messenger RNA transcribed therefrom, said antisense sequences adapted to bind to and inhibit transcription or translation of said target mutant cytochrome c oxidase genes without preventing transcription or translation of wild-type cytochrome c oxidase genes.  
     
     
         8 . The therapeutic composition of  claim 7 , wherein Alzheimer's disease is treated and wherein said cytochrome c oxidase genes contain mutations at one or more codons selected from the group of: 
 (a) codon 155, codon 167, codon 178, codon 193, codon 194, and codon 415 of the cytochrome c oxidase I gene; and    (b) codon 20, codon 22, codon 68, codon 71, codon 74, codon 90, codon 95, codon 110, and codon 146 of the cytochrome c oxidase II gene.    
     
     
         9 . A method for detecting the presence of Alzheimer's disease in a subject, comprising the steps of: 
 a) obtaining a biological sample containing mitochondria from said subject; and    b) interrogating at least one variant polypeptide, arising from one or more mutations in one or more subunits of mitochondrial cytochrome c oxidase genes, which correlates with the presence of Alzheimer's disease.    
     
     
         10 . The method of  claim 9 , wherein said mutation is interrogated using monoclonal antibodies or polyclonal antibodies.  
     
     
         11 . A ribozyme adapted to hybridize to and cleave mitochondrial mRNA molecules that encode for mutant cytochrome c oxidase subunits.