A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of a target gene via RNA interference, having a sense strand and an antisense strand and comprising formula: B-N X3 - X2 B -3' B X1 -N X4 - X5 -5' wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid 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 complementarity to the antisense strand; each N is independently a nucleotide which is unmodified or chemically modified or is optionally a non-nucleotide; each B is independently a terminal cap that is present or absent; represents overhanging nucleotides, each of which is independently unmodified or chemically modified; 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) all pyrimidine nucleotides in NX4 positions are 2'-O-methyl nucleotides; (b) all purine nucleotides in NX4 positions are 2'-deoxy-2'-fluoro nucleotides; (c) all pyrimidine nucleotides in NX3 positions are 2'-O-methyl nucleotides; (d) all purine nucleotides in NX3 positions are 2'-deoxy-2'-fluoro nucleotides; (e) position nucleotide(s) are any combination of ribonucleotides, deoxyribonucleotides, 2'-O-methyl nucleotides, or 2'-deoxy-2'-fluoro nucleotides; and (f) the nucleotide at position 14 from the 5'-end of the antisense strand of said double-stranded short interfering nucleic acid (siNA) molecule is a 2'-deoxy-2'-fluoro nucleotide. the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid 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 complementarity to the antisense strand; each N is independently a nucleotide which is unmodified or chemically modified or is optionally a non-nucleotide; each B is independently a terminal cap that is present or absent; represents overhanging nucleotides, each of which is independently unmodified or chemically modified; 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) all pyrimidine nucleotides in NX4 positions are 2'-O-methyl nucleotides; (b) all purine nucleotides in NX4 positions are 2'-deoxy-2'-fluoro nucleotides; (c) all pyrimidine nucleotides in NX3 positions are 2'-O-methyl nucleotides; (d) all purine nucleotides in NX3 positions are 2'-deoxy-2'-fluoro nucleotides; (e) position nucleotide(s) are any combination of ribonucleotides, deoxyribonucleotides, 2'-O-methyl nucleotides, or 2'-deoxy-2'-fluoro nucleotides; and (f) the nucleotide at position 14 from the 5'-end of the antisense strand of said double-stranded short interfering nucleic acid (siNA) molecule is a 2'-deoxy-2'-fluoro nucleotide. (a) all pyrimidine nucleotides in NX4 positions are 2'-O-methyl nucleotides; (b) all purine nucleotides in NX4 positions are 2'-deoxy-2'-fluoro nucleotides; (c) all pyrimidine nucleotides in NX3 positions are 2'-O-methyl nucleotides; (d) all purine nucleotides in NX3 positions are 2'-deoxy-2'-fluoro nucleotides; (e) position nucleotide(s) are any combination of ribonucleotides, deoxyribonucleotides, 2'-O-methyl nucleotides, or 2'-deoxy-2'-fluoro nucleotides; and (f) the nucleotide at position 14 from the 5'-end of the antisense strand of said double-stranded short interfering nucleic acid (siNA) molecule is a 2'-deoxy-2'-fluoro nucleotide.