Compositions and Methods for Treating Huntington's Disease and Related Disorders

Abstract

Compositions and methods are provided for the inhibition, treatment and/or prevention of Huntington's disease and related disorders.

What is claimed is: 
     
         1 . A method for inhibiting, treating, and/or preventing a polyglutamine disorder in a subject in need thereof, said method comprising reducing the expression of a mutant protein encoded by an allele of a gene associated with the polyglutamine disorder in said subject,
 wherein said polyglutamine disorder is characterized by an abnormally high number of cytosine-adenine-guanine (CAG) repeats resulting in an extended polyglutamine tract in the encoded for mutant protein, and   wherein said method comprising administering to the subject a nucleic acid molecule encoding Cas9 and at least one guide RNA.   
     
     
         2 . A method for reducing the expression of a mutant protein encoded by an allele of a gene associated with a polyglutamine disorder in a cell, said method comprising delivering to the cell a nucleic acid molecule encoding Cas9 and at least one guide RNA,
 wherein said polyglutamine disorder is characterized by an abnormally high number of cytosine-adenine-guanine (CAG) repeats resulting in an extended polyglutamine tract in the encoded for mutant protein.   
     
     
         3 . The method of  claim 1 , wherein said polyglutamine disorder is Huntington's disorder and said gene is the huntingtin (HTT) gene. 
     
     
         4 . The method of  claim 1 , wherein said method comprises administering to the subject a nucleic acid molecule encoding Cas9, at least one guide RNA, and, optionally at least one donor DNA. 
     
     
         5 . The method of  claim 1 , wherein said guide RNA are administered as a nucleic acid molecule encoding said guide RNA. 
     
     
         6 . The method of  claim 5 , wherein said nucleic acid molecules are administered in an expression vector. 
     
     
         7 . The method of  claim 6 , wherein said expression vector is a viral vector. 
     
     
         8 . The method of  claim 1 , wherein at least one guide RNA targets a sequence adjacent to a PAM present on only one allele of the gene. 
     
     
         9 . The method of  claim 8 , wherein said PAM is present only on the mutant allele. 
     
     
         10 . The method of  claim 1 , wherein two guide RNAs are administered. 
     
     
         11 . The method of  claim 10 , wherein at least one of the guide RNA targets a sequence adjacent to a PAM present on only one allele of the gene. 
     
     
         12 . The method of  claim 10 , wherein a first guide RNA targets a sequence within the promoter or 5′ untranslated region of the gene and a second guide RNA targets a sequence within the first intron of the gene. 
     
     
         13 . The method of  claim 10 , wherein the first guide RNA comprises sgHD1 and the second guide RNA comprises sgHDi3. 
     
     
         14 . An isolated guide RNA, wherein said guide RNA targets a sequence adjacent to a PAM present on only one allele of a gene associated with a polyglutamine disorder. 
     
     
         15 . A nucleic acid molecule encoding at least one of the guide RNA of  claim 14 . 
     
     
         16 . A vector comprising the nucleic acid molecule of  claim 15 . 
     
     
         17 . The vector of  claim 16 , which is a viral vector. 
     
     
         18 . The vector of  claim 16 , further comprising a nucleic acid molecule encoding Cas9. 
     
     
         19 . A composition comprising at least one nucleic acid molecule of  claim 15  and a carrier. 
     
     
         20 . A composition comprising at least one guide RNA of  claim 14  and a carrier.