Compositions and methods for treating huntington's disease

An adeno-associated viral (AAV) vector comprising a nucleic acid sequence positioned between two inverted terminal repeats (ITRs), wherein said nucleic acid sequence comprises

• (a) a stem and loop to form a stem-loop structure, the sequence of said stem-loop structure from 5′ to 3′ comprising:
• i. a UG motif at or near the base of the 5′ stem of the stem-loop structure;
• ii. a 5′ stem arm comprising a sense strand and optional 5′ spacer region, wherein said 5′ spacer region, when present, is located between said UG motif and said sense strand;
• iii. a loop region comprising a UGUG motif at the 5′ end of said loop region;
• iv. a 3′ stem arm comprising an antisense strand and optionally a 3′ spacer region, wherein a uridine is present at the 5′ end of said antisense strand and wherein said 3′ spacer region, when present, has a length sufficient to form one helical turn;
• (b) a first flanking region located 5′ to said stem-loop structure;
• and
• (c) a second flanking region located 3′ to said stem-loop structure, said second region comprising a CNNC motif,
• wherein said antisense strand and said sense strand form a siRNA duplex that when expressed inhibits or suppresses the expression of HTT in a cell, wherein the sense strand sequence comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of sequences listed in Table 3, Table 4, or Table 5 and the antisense strand sequence comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of sequences listed in Table 3, Table 4, or Table 5 and wherein said sense strand sequence and antisense strand sequence share a region of complementarity of at least four nucleotides in length.