Inhibition of RNA-mediated gene expression using short interference nucleic acids (ANic)

摘要

A composition comprising: I) a double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of a target gene through RNA interference, which has a coding chain and a non-coding chain and comprises the formula ( A): Wherein, the top chain is the coding chain and the bottom chain is the non-coding chain of the double-stranded nucleic acid molecule; wherein the non-coding strand comprises a sequence having at least 15 nucleotides that are complementary to a target RNA sequence encoded by the target gene and the coding strand comprises a sequence that is complementary to the non-coding strand; each N is independently a nucleotide that is unmodified or chemically modified, or is optionally a non-nucleotide; each B is independently a terminal cap that is present or absent; (N) represents extension nucleotides, each of which is independently unmodified or chemically modified; [N] represents nucleotides at the 5 'end of the non-coding chain; 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 of the pyrimidine nucleotides at positions NX4 are 2'-O-methyl nucleotides; (b) all purine nucleotides at positions NX4 are 2'-fluoro nucleotides; (c) all pyrimidine nucleotides at positions NX3 are 2'-O-methyl nucleotides; (d) all purine nucleotides at positions NX3 are 2'-fluoro nucleotides; (e) the nucleotide or nucleotides at position [N] are any combination of ribonucleotides, deoxyribonucleotides, 2'-O-methyl nucleotides or 2'-fluoro nucleotides; and (f) the nucleotide at position 14 from the 5 'end of the non-coding strand of said double stranded short interference nucleic acid (siNA) molecule is a 2'-deoxy-2'-fluoro nucleotide; and II) a cationic lipid comprising (13Z, 16Z) -N, N-dimethyl-3-nonyldocosa-13,16-dien-1-amine.