RNAi-mediated inhibition of phosphodiesterase type 4 for treatment of CAMP-related ocular disorders
RNA interference is provided for inhibition of phosphodiesterase type 4 mRNA expression for treating patients with a cAMP-related ocular disorder. Phosphodiesterase type 4 mRNA targets include mRNA for 4A, 4B, 4C, and 4D phosphodiesterase isoforms.
1. An interfering RNA for inhibiting the expression of Phosphodiesterase type-IV (PDE4) mRNA, wherein the interfering RNA comprises a sense strand and an antisense strand each 19-49 nucleotides in length, wherein the sense strand comprises the base sequence of any of SEQ ID NOs: 146, 149-158, 161, 167, 169-171, or 173-199 except that each thymine (T) nucleotide in the sequence can independently be thymine (T) or uracil (U), and the antisense strand comprises a nucleotide sequence that is complementary to the sense strand.
2. The interfering RNA of claim 1 , wherein each strand of the interfering RNA is 19 to 27 nucleotides in length.
3. The interfering RNA of claim 1 , wherein the interfering RNA comprises one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages.
4. The interfering RNA of claim 3 , wherein the interfering RNA comprises one or more chemically modified nucleotides having a 2′ amino group, a 2′ O-methyl group, or a 2′ methoxyethyl group.
5. The interfering RNA of claim 3 , wherein the interfering RNA comprises one or more chemically modified nucleotides having a modification on the sugar portion and one or more chemically modified nucleotides having a non-phosphodiester linkage.
6. The interfering RNA of claim 3 , wherein non-nucleotide material is bound to the 5′ terminal end and/or 3′ terminal end of the sense strand and/or the antisense strand.
7. The interfering RNA of claim 3 , wherein non-nucleotide material is bound internally to the sense strand and/or the antisense strand, wherein the non-nucleotide material is bound at a position on the strand that is not the 5′ terminal end or the 3′ terminal end of a terminal nucleotide or nucleoside.
8. The interfering RNA of claim 6 , wherein the non-nucleotide material improves cellular uptake, enhances cellular targeting, assists in tracing, improves stability, and/or reduces activation of the interferon pathway.
9. The interfering RNA of claim 3 , wherein the sense strand and/or the antisense strand contains a 3′ overhang.
10. The interfering RNA of claim 3 , wherein the sense strand and/or the antisense strand contains a 5′ overhang.
11. The interfering RNA of claim 3 , wherein the interfering RNA has at least one blunt end.
12. A composition for inhibiting the expression of PDE4 mRNA, comprising the interfering RNA of claim 1 , and a pharmaceutically acceptable carrier.
13. The composition of claim 12 , wherein the interfering RNA comprises one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages.
14. The composition of claim 13 , wherein the interfering RNA comprises one or more chemically modified nucleotides having a 2′ amino group, a 2′ O-methyl group, or a 2′ methoxyethyl group.
15. The composition of claim 13 wherein the interfering RNA comprises one or more chemically modified nucleotides having a modification on the sugar portion and one or more chemically modified nucleotides having a non-phosphodiester linkage.
16. The composition of claim 13 , wherein non-nucleotide material is bound to the 5′ terminal end and/or 3′ terminal end of the sense strand and/or the antisense strand.
17. The composition of claim 13 , wherein non-nucleotide material is bound internally to the sense strand and/or the antisense strand, wherein the non-nucleotide material is bound at a position on the strand that is not the 5′ terminal end or the 3′ terminal end of a terminal nucleotide or nucleoside.
18. The composition of claim 16 , wherein the non-nucleotide material improves cellular uptake, enhances cellular targeting, assists in tracing, improves stability, and/or reduces activation of the interferon pathway.
19. The composition of claim 13 , wherein the sense strand and/or the antisense strand contains a 3′ overhang.
20. The composition of claim 13 , wherein the sense strand and/or the antisense strand contains a 5′ overhang.
21. The composition of claim 13 , wherein the interfering RNA has at least one blunt end.