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 nucleic acid molecule, wherein:
 (a) the nucleic acid molecule comprises a sense strand and a separate antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides;   (b) each strand of the nucleic acid molecule is independently 18 to 27 nucleotides in length;   (c) an 18 to 27 nucleotide sequence of the antisense strand is complementary to a human tumor necrosis factor (TNF) receptor RNA sequence comprising SEQ ID NO: 373;   (d) an 18 to 27 nucleotide sequence of the sense strand is complementary to the antisense strand and comprises an 18 to 27 nucleotide sequence of the human TNF receptor RNA sequence; and   (e) 50 percent or more of the nucleotides in at least one strand comprise a 2-sugar modification, wherein the 2′-sugar modification of any of the pyrimidine nucleotides differs from the 2′-sugar modification of any of the purine nucleotides.   
     
     
         2 . The nucleic acid molecule of  claim 1 , wherein 50 percent or more of the nucleotides in each strand comprise a 2′-sugar modification. 
     
     
         3 . The nucleic acid molecule of  claim 1 , wherein the 2′-sugar modification is selected from the group consisting of 2′-deoxy-2′-fluoro, 2′-O-methyl, and 2′-deoxy. 
     
     
         4 . The nucleic acid of  claim 3 , wherein the 2′-deoxy-2′-fluoro sugar modification is a pyrimidine modification. 
     
     
         5 . The nucleic acid of  claim 3 , wherein the 2′-deoxy sugar modification is a pyrimidine modification. 
     
     
         6 . The nucleic acid of  claim 3 , wherein the 2′-O-methyl sugar modification is a pyrimidine modification. 
     
     
         7 . The nucleic acid molecule of  claim 4 , wherein said pyrimidine modification is in the sense strand, the antisense strand, or both the sense strand and antisense strand. 
     
     
         8 . The nucleic acid molecule of  claim 6 , wherein said pyrimidine modification is in the sense strand, the antisense strand, or both the sense strand and antisense strand. 
     
     
         9 . The nucleic acid molecule of  claim 3 , wherein the 2′-deoxy sugar modification is a purine modification. 
     
     
         10 . The nucleic acid molecule of  claim 3 , wherein the 2′-O-methyl sugar modification is a purine modification. 
     
     
         11 . The nucleic acid molecule of  claim 9 , wherein the purine modification is in the sense strand. 
     
     
         12 . The nucleic acid molecule of  claim 10 , wherein the purine modification is in the antisense strand. 
     
     
         13 . The nucleic acid molecule of  claim 1 , wherein the nucleic acid molecule comprises ribonucleotides. 
     
     
         14 . The nucleic acid molecule of  claim 1 , wherein the sense strand includes a terminal cap moiety at the 5′-end, the 3′-end, or both of the 5′- and 3′-ends. 
     
     
         15 . The nucleic acid molecule of  claim 14 , wherein the terminal cap moiety is an inverted deoxy abasic moiety. 
     
     
         16 . The nucleic acid molecule of  claim 1 , wherein said nucleic acid molecule includes one or more phosphorothioate internucleotide linkages. 
     
     
         17 . The nucleic acid molecule of  claim 16 , wherein one of the phosphorothioate internucleotide linkages is at the 3′-end of the antisense strand. 
     
     
         18 . The nucleic acid molecule of  claim 1 , wherein the 5′-end of the antisense strand includes a terminal phosphate group. 
     
     
         19 . The nucleic acid molecule of  claim 1 , wherein the sense strand, the antisense strand, or both the sense strand and the antisense strand include a 3′-overhang. 
     
     
         20 . A composition comprising the nucleic acid molecule of  claim 1 , in a pharmaceutically acceptable carrier or diluent.