RNAi-related inhibition of TNF-alpha signaling pathway for treatment of ocular angiogenesis
View Patent ↗RNA interference is provided for inhibition of tumor necrosis factor α (TNFα) by silencing TNFα cell surface receptor TNF receptor-1 (TNFR1) mRNA expression, or by silencing TNFα converting enzyme (TACE/ADAM17) mRNA expression. Silencing such TNFα targets, in particular, is useful for treating patients having a TNFα-related condition or at risk of developing a TNFα-related condition, such as ocular angiogenesis, retinal ischemia, and diabetic retinopathy.
1. A double-stranded interfering RNA molecule comprising:
(a) a sense strand comprising any one of SEQ ID NO:3, SEQ ID NOs: 14-58 and SEQ ID NOs: 155-201, except that the T's can be T's or U's, and
(b) an antisense strand complementary to any one of SEQ ID NO: 3, SEQ ID NOs: 14-58 and SEQ ID NOs: 155-201;
and wherein the sense strand and the antisense strand are each 19-49 nucleotides in length.
2. The compositions of claim 1 , wherein each strand of the interfering RNA molecule is independently 19 to 27 nucleotides in length.
3. The composition of claim 2 , wherein each strand of the interfering RNA molecule is independently 19 to 25 nucleotides in length.
4. The composition of claim 3 , wherein each strand of the interfering RNA molecule is independently 19 to 21 nucleotides in length.
5. The composition of claim 1 , wherein the sense and antisense strands are connected by a linker to form a shRNA.
6. The composition of claim 1 , wherein the interfering RNA molecule has blunt ends.
7. The composition of claim 1 , wherein at least one strand of the interfering RNA molecule comprises a 3′ overhang.
8. The composition of claim 7 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides.
9. The composition of claim 8 , wherein the 3′ overhang comprises 2 nucleotides.
10. The composition of claim 1 , wherein the interfering RNA molecule comprises at least one modification.
11. The composition of claim 1 wherein the interfering RNA molecule sense strand and/or antisense strand contains one or more chemically modified nucleotides.
12. The composition of claim 1 wherein the interfering RNA molecule has at least one blunt end.
13. The composition of claim 11 wherein the chemically modified nucleotide comprises a ribose 2′-OH modification.
14. The composition of claim 13 wherein the ribose 2′-OH modification is selected from the group consisting of: 2′-amino group, 2′-O-methyl group, 2′-methoxyethyl group, and 2′-O,4′-C methylene bridge.
15. The composition of claim 1 the a phosphate group of a sense strand and/or antisense strand nucleotide is modified by substituting one or more of the oxygens of the phosphate group with nitrogen or with sulfur.
16. The composition of claim 1 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA.