Compositions and methods for treatment of friedreich's ataxia

Abstract

Described are compounds and methods useful for the treatment and investigation of Friedreich's Ataxia.

1 . A double-stranded oligonucleotide of 13 to 22 nucleobases in length and having a repeating tri-nucleobase sequence comprising (i) GAA or CUU or (ii) AAG or UUC. 
     
     
         2 . The double-stranded oligonucleotide of  claim 1 , wherein said oligonucleotide comprises one or more chemically-modified nucleobases. 
     
     
         3 . The double-stranded oligonucleotide of  claim 2 , wherein said one or more chemically-modified nucleobases is a nuclease-resistant modification. 
     
     
         4 . The double-stranded oligonucleotide of  claim 3 , wherein said nuclease-resistant modification is a modified sugar moiety or a modified internucleoside linkage. 
     
     
         5 . The double-stranded oligonucleotide of  claim 4 , wherein said modified sugar moiety is a high-affinity sugar modification. 
     
     
         6 . The double-stranded oligonucleotide of  claim 5 , wherein the high-affinity sugar modification is a bicyclic sugar moiety or a 2′-modified sugar moeity. 
     
     
         7 . (canceled) 
     
     
         8 . The double-stranded oligonucleotide of  claim 4 , wherein the modified sugar moiety is a 4′ to 2′ bicyclic sugar moiety. 
     
     
         9 - 12 . (canceled) 
     
     
         13 . The double-stranded oligonucleotide of  claim 1 , wherein said double-stranded oligonucleotide comprises terminal dT residues. 
     
     
         14 . The double-stranded oligonucleotide of  claim 1 , wherein said double-stranded oligonucleotide comprises 3′ and/or ‘5 2’-O-methyl modifications. 
     
     
         15 . The double-stranded oligonucleotide of  claim 1 , wherein said double-stranded oligonucleotide comprises (a) a central mismatch (within bases 9-14) with a target sequence comprising said repeating tri-nucleobase sequence, or (b) a mismatch outside of the seed sequence (bases 2-8 within the guide strand complementary to the GAA target sequence). 
     
     
         16 . The double-stranded oligonucleotide of  claim 1 , wherein the double-stranded oligonucleotide comprises 4, 5, 6 or 7 repeats. 
     
     
         17 . The double-stranded oligonucleotide of  claim 1 , wherein the nucleosides are linked by phosphate internucleoside linkages. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The double-stranded oligonucleotide of  claim 1 , wherein said double-stranded oligonucleotide comprises DNA nucleobases, RNA nucleobases or a mixture of DNA and RNA nucleobases. 
     
     
         21 . A method of selectively increasing the expression of a Frataxin transcript comprising contacting a cell having an expanded GAA repeat region with a double-stranded oligonucleotide of  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein the expanded GAA repeat region contains 60 or more repeats. 
     
     
         23 . The method of  claim 21 , wherein the expanded GAA repeat region contains 66 to 1700 repeats. 
     
     
         24 . The method of  claim 21 , where said cell is contacted with said double-stranded oligonucleotide at about 5-75 nM. 
     
     
         25 . The method of  claim 21 , wherein the cell is located in a subject suffering from Friedreich's Ataxia. 
     
     
         26 . The method of  claim 20 , wherein contacting comprises administering said double-stranded oligonucleotide by direct administration into the central nervous system, cerebrospinal fluid, or mediated uptake across the blood brain barriers, and/or administering said double-stranded oligonucleotide more than once. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 20 , further comprising administering a second therapeutic agent to said subject. 
     
     
         29 . The method of  claim 23 , wherein said second therapeutic agent modulates histone acetylation. 
     
     
         30 . The method of  claim 29 , wherein said second therapeutic agent is a histone deacetylase inhibitor.