Treatment of age-related macular degeneration using RNA complexes that target MYD88 or TLR3
In certain aspects, provided herein are RNA complexes that inhibit Myeloid differentiation primary response gene 88 (MyD88) and/or Toll-like receptor 3 (TLR3) and are useful in the treatment of age-related macular degeneration (AMD). In certain aspects, provided herein are pharmaceutical compositions comprising such RNA complexes and methods of using such RNA complexes and pharmaceutical compositions.
1. An RNA duplex of an antisense strand of at least 19 nucleotides (nt) in length and a sense strand of 16 nt in length, wherein:
the sequence of the antisense strand comprises SEQ ID NO: 54 or SEQ ID NO: 56;
the sequence of the sense strand is SEQ ID NO: 53 or SEQ ID NO: 55;
a cholesterol moiety is attached to the 3′ end of the sense strand; and
the antisense strand and the sense strand form a complex in which the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end.
2. The RNA duplex of claim 1 , wherein the antisense strand is 19 to 21 nt in length.
3. The RNA duplex of claim 1 , wherein the antisense strand is 24 to 121 nt in length.
4. The RNA duplex of claim 1 , wherein the RNA duplex is capable of inhibiting MyD88 expression by a cell.
5. The RNA duplex of claim 1 , wherein the RNA duplex further comprises a 2′-O-methylated nucleoside or a phosphorothioate bond.
6. The RNA duplex of claim 5 , wherein the RNA duplex comprises a 2′-O-methylated nucleoside positioned at the 3′ end of the sense strand or at the 3′ end of the antisense strand.
7. The RNA duplex of claim 5 , wherein the RNA duplex comprises a phosphorothioate bond.
8. The RNA duplex of claim 5 , wherein the RNA duplex is capable of penetrating the cellular membrane of a cell in the absence of a delivery vehicle.
9. A method of inhibiting MyD88 expression by a cell, comprising contacting the cell with an RNA duplex of claim 1 .
10. A pharmaceutical composition comprising an RNA duplex of claim 1 and a pharmaceutically acceptable carrier.
11. The RNA duplex of claim 1 , wherein the sequence of the antisense strand is SEQ ID NO: 54 or SEQ ID NO: 95, and sequence of the sense strand is SEQ ID NO: 53.
12. The RNA duplex of claim 1 , wherein the sequence of the antisense strand is SEQ ID NO: 56 or SEQ ID NO: 98, and the sequence of the sense strand is SEQ ID NO: 55.
13. The RNA duplex of claim 2 , wherein the RNA duplex comprises a 2′-O-methylated nucleoside positioned at the 3′ end of the sense strand or at the 3′ end of the antisense strand.
14. The RNA duplex of claim 2 , wherein the RNA duplex comprises a phosphorothioate bond.
15. The RNA duplex of claim 2 , wherein the RNA duplex is capable of penetrating the cellular membrane of a cell in the absence of a delivery vehicle.
16. The RNA duplex of claim 2 , wherein the RNA duplex is capable of inhibiting MyD88 expression by a cell.
17. The RNA duplex of claim 3 , wherein the RNA duplex comprises a 2′-O-methylated nucleoside positioned at the 3′ end of the sense strand or at the 3′ end of the antisense strand.
18. The RNA duplex of claim 3 , wherein the RNA duplex comprises a phosphorothioate bond.
19. The RNA duplex of claim 11 , wherein the RNA duplex further comprises a 2′-O-methylated nucleoside or a phosphorothioate bond.
20. The RNA duplex of claim 12 , wherein the RNA duplex further comprises a 2′-O-methylated nucleoside or a phosphorothioate bond.