RNA INTERFERENCE MEDIATED INHIBITION OF TNF AND TNF RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)

Abstract

This invention relates to compounds, compositions, and methods useful for modulating tumor necrosis factor and/or tumor necrosis factor receptor gene expression using short interfering nucleic acid (siNA) molecules. This invention also relates to compounds, compositions, and methods useful for modulating the expression and activity of other genes involved in pathways of tumor necrosis factor and/or tumor necrosis factor receptor gene expression and/or activity by RNA interference (RNAi) using small nucleic acid molecules. In particular, the instant invention features small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of tumor necrosis factor and/or tumor necrosis factor receptor genes, (TNF and/or TNF receptor).

1 . A chemically modified double stranded nucleic acid molecule that mediates RNA interference (RNAi) against a target tumor necrosis factor (TNF) receptor RNA sequence, wherein:
 a) the nucleic acid molecule comprises a sense strand and a separate antisense strand;   b) each strand of the nucleic acid molecule is independently 18 to 24 nucleotides in length;   c) the antisense strand is complementary to the target tumor necrosis factor (TNF) receptor RNA sequence;   d) a plurality of pyrimidine nucleotides in both the sense strand and the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides, a plurality of purine nucleotides in the sense strand are ribonucleotides, and a plurality of purine nucleotides in the antisense strand are 2′-O-methyl purine nucleotides.   
     
     
         2 . The nucleic acid molecule of  claim 1 , wherein one or more of the chemically modified nucleotides are phosphorothioate linked nucleotides. 
     
     
         3 . The nucleic acid molecule of  claim 1 , further comprising inverted deoxy abasic modifications at the 3′-end, the 5′-end, or both the 3′- and 5′-ends of the sense strand. 
     
     
         4 . The nucleic acid molecule of  claim 1 , wherein the sense strand comprises a 3′-overhang of 1-4 nucleotides.