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 the neural cell for a time sufficient to allow uptake of the iRNA agent into the cell, wherein (i) the iRNA agent comprises a sense and an antisense strand that form an RNA duplex, and (ii) 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 . A method of downregulating expression of a target gene in a neural cell, the method comprising contacting an iRNA agent with the neural cell for a time sufficient to allow uptake of the iRNA agent into the cell, 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. 
     
     
         3 . The method of  claim 1  or  2 , wherein the cells are contacted for a time sufficient to allow axonal transport of said iRNA. 
     
     
         4 . The method of  claim 1 , wherein the iRNA agent comprises a lipophilic moiety. 
     
     
         5 . The method of  claim 4 , wherein the lipophilic moiety is a cholesterol. 
     
     
         6 . The method of  claim 4 , wherein the lipophilic moiety is conjugated to the sense strand. 
     
     
         7 . The method of  claim 4 , wherein the lipophilic moiety is conjugated to the 3′ end of the sense strand. 
     
     
         8 .- 12 . (canceled) 
     
     
         13 . A method of treating a human comprising identifying a human having or at risk for developing a neurological disorder, the method comprising 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, and (ii) 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. 
     
     
         14 . 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, 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. 
     
     
         15 . The method of  claim 13 , wherein the iRNA agent comprises a lipophilic moiety. 
     
     
         16 . The method of  claim 15 , wherein the lipophilic moiety is a cholesterol. 
     
     
         17 . The method of  claim 15 , wherein the lipophilic moiety is conjugated to the sense strand. 
     
     
         18 . The method of  claim 15 , wherein the lipophilic moiety is conjugated to the 3′ end of the sense strand. 
     
     
         19 . The method of  claim 15 , wherein the iRNA agent further comprises a phosphorothioate or a 2′-OMe modification. 
     
     
         20 .- 33 . (canceled) 
     
     
         34 . 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 1.   
     
     
         35 . The method of  claim 34 , wherein the iRNA agent further comprises a lipophilic moiety. 
     
     
         36 . The method of  claim 35 , wherein the cells are contacted for a time sufficient to allow axonal transport of said iRNA. 
     
     
         37 . The method of  claim 36 , wherein the iRNA agent further comprises a phosphorothioate or a 2′-OMe modification. 
     
     
         38 .- 42 . (canceled) 
     
     
         43 . An isolated iRNA agent comprising 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 1, and wherein the iRNA agent comprises a lipophilic moiety. 
     
     
         44 . The iRNA agent of  claim 43 , wherein the lipophilic moiety is a cholesterol molecule. 
     
     
         45 . The iRNA agent of  claim 43 , wherein the lipophilic moiety is attached to the sense strand. 
     
     
         46 . The iRNA agent of  claim 43 , wherein the lipophilic moiety is attached to the 3′ end of the sense strand. 
     
     
         47 .- 51 . (canceled) 
     
     
         52 . A pharmaceutical composition, comprising:
 the iRNA agent  claim 43 ; and   a pharmaceutically acceptable carrier.   
     
     
         53 .- 56 . (canceled) 
     
     
         57 . A method of evaluating an iRNA agent for enhanced uptake into neural cells comprising: providing a candidate iRNA agent conjugated to a lipophilic agent, wherein the iRNA agent is in a solution that does not contain a transfection reagent, contacting the iRNA agent with a neural cell for a time sufficient for uptake into the neural cell and determining if the iRNA agent is taken up by the neural cell. 
     
     
         58 .- 66 . (canceled)