Methods and compositions for treating neurological disease

Abstract

This invention relates to methods and compositions for treating neurological disease, and more particularly to methods of delivering iRNA agents to neural cells for the treatment of neurological diseases.

1 . A method of downregulating expression of a target gene in a neural cell distal to the site of administration, the method comprising contacting an iRNA agent with neural cells for a time sufficient to allow uptake of the iRNA agent into the cells and axonal transport of said iRNA, wherein (i) the iRNA agent comprises a sense and an antisense strand that form an RNA duplex, (ii) the iRNA agent comprises a lipophilic moiety, and (iii) the sequence of the antisense strand of the iRNA agent comprises a nucleotide sequence sufficiently complementary to a target sequence of about 18 to 25 nucleotides of an RNA expressed from the target gene.  
     
     
         2 . The method of  claim 1 , wherein the lipophilic moiety is a cholesterol.  
     
     
         3 . The method of  claim 1 , wherein the lipophilic moiety is conjugated to the sense strand.  
     
     
         4 . The method of  claim 1 , wherein the lipophilic moiety is conjugated to the 3′ end of the sense strand.  
     
     
         5 . The method of  claim 1 , wherein the antisense sequence differs by no more than four nucleotides from an antisense sequence listed in Table 2.  
     
     
         6 . The method of  claim 1 , wherein the antisense strand is selected from an antisense strand listed in Table 2.  
     
     
         7 . The method of  claim 1 , wherein the iRNA agent further comprises a phosphorothioate or a 2′-OMe modification.  
     
     
         8 . The method of  claim 1 , wherein the iRNA agent is provided in a solution that lacks a transfection reagent.  
     
     
         9 . A method of treating a human comprising identifying a human having or at risk for developing a neurological disorder, and administering to the human an iRNA agent that targets a gene expressed in a neural cell distal to the site of administration, wherein the expression of the gene is associated with symptoms of the neurological disorder, and wherein (i) the iRNA agent comprises a sense and an antisense strand that form an RNA duplex, (ii) the iRNA agent comprises a lipophilic moiety, and (iii) the antisense strand of the iRNA agent comprises a nucleotide sequence sufficiently complementary to a target sequence of about 18 to 25 nucleotides of an RNA expressed from the target gene.  
     
     
         10 . The method of  claim 9 , wherein the lipophilic moiety is a cholesterol.  
     
     
         11 . The method of  claim 9 , wherein the lipophilic moiety is conjugated to the sense strand.  
     
     
         12 . The method of  claim 9 , wherein the lipophilic moiety is conjugated to the 3′ end of the sense strand.  
     
     
         13 . The method of  claim 9 , wherein the iRNA agent further comprises a phosphorothioate or a 2′-OMe modification.  
     
     
         14 . The method of  claim 9 , wherein the antisense sequence differs by no more than four nucleotides from an antisense sequence listed in Table 2.  
     
     
         15 . The method of  claim 9 , wherein the antisense strand is selected from an antisense strand listed in Table 2.  
     
     
         16 . The method of  claim 9 , wherein the antisense strand of the iRNA agent comprises a sequence complementary to a sequence comprising a polymorphism of a huntingtin (htt) RNA.  
     
     
         17 . The method of  claim 9 , wherein the human carries a genetic variation in a Parkin gene or a ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene.  
     
     
         18 . The method of  claim 9 , wherein the neurological disorder is Huntington's disease.  
     
     
         19 . The method of  claim 9 , wherein the neurological disorder is Parkinson's disease.  
     
     
         20 . The method of  claim 9 , wherein the neurological disorder is Alzheimer's Disease, multiple system atrophy, or Lewy body dementia.  
     
     
         21 . The method of  claim 7 , wherein the iRNA agent comprises a nucleotide overhang having 1 to 4 unpaired nucleotides.  
     
     
         22 . The method of  claim 9 , wherein the iRNA agent is provided in a solution that lacks a transfection reagent.  
     
     
         23 . A method of reducing the amount of huntingtin (htt) RNA in a neural cell of a subject, comprising: 
 contacting the neural cell with an iRNA agent, wherein said neural cell is distal to the site of action and the iRNA agent comprises a sense and an antisense strand, wherein the sense and the antisense strands form an RNA duplex, wherein the antisense strand comprises a nucleotide sequence that differs by no more than four nucleotides from an antisense sequence listed in Table 2, and wherein the iRNA agent comprises a lipophilic moiety.    
     
     
         24 . The method of  claim 23 , wherein the iRNA agent further comprises a phosphorothioate or a 2′-OMe modification.  
     
     
         25 . The method of  claim 23 , wherein the iRNA agent comprises an antisense strand comprising a sequence selected from the antisense strands listed in Table 2.  
     
     
         26 . The method of  claim 23 , wherein the iRNA agent comprises a sense strand selected from the sense strands listed in Table 2.  
     
     
         27 . The method of  claim 23 , wherein the iRNA agent comprises an antisense strand comprising a sequence complementary to sequence comprising a polymorphism of an htt RNA.  
     
     
         28 . The method of  claim 27 , wherein the polymorphism is an A to C at position 171 according to the sequence of GenBank Accession No. NM — 002111.  
     
     
         29 . The method of  claim 23 , wherein the iRNA agent comprises a nucleotide overhang having 1 to 4 unpaired nucleotides.