RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)

A compound comprising:

• I) a double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of a target gene via RNA interference, comprising a sense strand and an antisense strand, said siNA molecule comprising formula (A):
• wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the siNA molecule;
• wherein the antisense strand comprises a sequence having at least 15 nucleotides that are complementary to a target RNA sequence encoded by the target gene and the sense strand comprises a sequence that is complementary to the antisense strand;
• each N is independently a nucleotide which is unmodified or chemically modified, or is a non-nucleotide;
• each B is independently a terminal cap;
• (N) represents overhanging nucleotides, each of which is independently unmodified or chemically modified;
• [N] represents nucleotides at the 5′-terminus of the antisense strand;
• X1 and X2 are independently integers from 0 to 4;
• X3 is an integer from 15 to 30;
• X4 is an integer from 12 to 27;
• and X5 is an integer from 1-6, provided that the sum of X4 and X5 is an integer from 15-30;
• and wherein
• (a) five or more pyrimidine nucleotides in NX4 positions are a combination of two or more of independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′deoxy nucleotides, ribonucleotides, or any combination thereof;
• (b) five or more purine nucleotides in NX4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′deoxy nucleotides, ribonucleotides, or any combination thereof;
• (c) five or more pyrimidine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′deoxy nucleotides, ribonucleotides, or any combination thereof;
• (d) five or more purine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′deoxy nucleotides, ribonucleotides;
• (e) [N] position nucleotide(s) are ribonucleotides, deoxyribonucleotides, 2′-O-alkyl nucleotides, or 2′-halo nucleotides, or any combination thereof irrespective of purine or pyrimidine content;
• and
• (f) the nucleotide at position 14 from the 5′-end of the antisense strand is a 2′-deoxy-2′-fluoro nucleotide regardless of whether it is a purine or pyrimidine;
• and
• II) a ligand covalently attached to the siNA molecule.