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. A method of treating age-related macular degeneration (AMD) in a subject, comprising administering to the subject 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 method of claim 1 , wherein the antisense strand is 19 to 21 nt in length.
3. The method of claim 1 , wherein the antisense strand is 24 to 121 nt in length.
4. The method of claim 1 , wherein the RNA duplex is capable of inhibiting MyD88 expression by a cell.
5. The method of claim 1 , wherein the RNA duplex is delivered to cells using a delivery vehicle.
6. The method of claim 1 , wherein the RNA duplex further comprises a 2′-O-methylated nucleoside and/or a phosphorothioate bond.
7. The method of claim 6 , wherein the RNA duplex comprises a 2′-O-methylated nucleoside positioned at the 3′ end of the sense strand and/or at the 3′ end of the antisense strand.
8. The method of claim 6 , wherein the RNA duplex comprises a phosphorothioate bond.
9. The method of claim 1 , wherein the RNA duplex is capable of penetrating the cellular membrane of a cell in the absence of a delivery vehicle.
10. The method 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.
11. The method 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.
12. The method of claim 3 , wherein the RNA duplex comprises a 2′-O-methylated nucleoside positioned at the 3′ end of the sense strand and/or at the 3′ end of the antisense strand.
13. The method of claim 1 , wherein the AMD is wet AMD.
14. The method of claim 1 , wherein the AMD is dry AMD.
15. The method of claim 1 , comprising administering a second agent for treatment of AMD.
16. The method of claim 15 , wherein the second agent is an anti-vascular endothelial growth factor (VEGF) therapeutic.
17. The method of claim 1 , comprising administering the RNA complex duplex to the eye of the subject.
18. The method of claim 1 , wherein the RNA complex duplex is administered by intravitreal injection.
19. The method of claim 1 , wherein the RNA duplex is administered as a pharmaceutically acceptable formulation.