RNA interference in ocular indications

1. A method for delivering a nucleic acid to an eye of a subject in need thereof, comprising

administering to the eye of the subject an sd-rxRNA®, in an effective amount to promote RNA interference by the sd-rxRNA® in the eye,

wherein the sd-rxRNA® comprises a guide strand and a passenger strand, wherein the sd-rxRNA® includes a double stranded region and a single stranded region, wherein the double stranded region is 8-15 nucleotides long, wherein the single stranded region is at the 3′ end of the guide strand and is 4-12 nucleotides long, wherein the single stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphorothioate modifications, wherein at least 40% of the nucleotides of the sd-rxRNA® are modified,

wherein the sd-rxRNA® is directed against a gene encoding TGFβ1 or TGFβ2, and wherein the sd-rxRNA comprises at least 12 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1027-1314.

2. The method of claim 1 , wherein the administration of the sd-rxRNA® is intravitreal.

3. The method of claim 1 , wherein the method is a method for treating an ocular disorder, optionally wherein the ocular disorder is selected from the group consisting of: vascular leakage, neovascularization, age-related macular degeneration (AMD), choroidal neovascularization (wet AMD), geographic atrophy (advanced dry AMD), early-to-intermediate dry AMD, post surgical cystoid macular edema (CME), nonproliferative diabetic retinopathy (NPDR), diabetic macular edema (DME), macular edema secondary to retinal vein occlusion (RVO), proliferative diabetic retinopathy (PDR), glaucoma, neovascular glaucoma (NVG), retinopathy of prematurity (ROP), fibroproliferative retinal disease, proliferative vitreoretinopathy (PVR), epiretinal membranes/vitreomacular adhesions, retinal degenerative disease, retinitis pigmentosa, retinal vascular occlusive disorders, retinal vein occlusion, retinal artery occlusion, retinoblastoma, trabeculectomy failure due to scarring, and uveitis.

4. The method of claim 3 , wherein the ocular disorder is proliferative vitreoretinopathy (PVR).

5. The method of claim 1 , wherein two or more different sd-rxRNA® molecules that are directed against genes encoding for two or more different proteins are both administered to the eye of the subject.

6. The method of claim 5 , wherein the sd-rxRNA® molecules comprise sd-rxRNA® molecules directed against VEGF and TGFβ1 and/or TGFβ2.

7. The method of claim 6 , wherein the sd-rxRNA® that is directed against VEGF is directed against a sequence comprising at least 12 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOS: 1-182, 1315-1376, and 1379-1398.

8. The method of claim 1 , wherein the sense strand of the sd-rxRNA® comprises at least 12 contiguous nucleotides of the group consisting of SEQ ID NOs: 1155 (mU*mC*mA.mU.mC.mA.mG.mU.mG.mU.mU*mA*mA.TEG-Chl), 1157 (mU*mC*mA.mU.mC.mA.mG.mU.mG.mU.mU*mA*mA.TEG-Chl), and 1313 (mC*mA*mC.mA.mC.mA.mG.mC.mA.mU.mA*mU*mA.TEG-Chl).

9. The method of claim 1 , wherein the antisense strand of the sd-rxRNA® comprises at least 12 contiguous nucleotides of the group consisting of SEQ ID NOs: 1156 (P.mU.fU. A. A.fC. A.fC.fU. G. A.fU. G. A* A*fC*fC*mA*mA* G.), 1158 (P.mU.fU. A. A.fC. A.fC.fU. G. A.fU. G.mA*mA*fC*fC*mA*mA* G.), and 1314 (P.mU. A.fU. A.fU. G.fC.fU. G.fU. G.fU.mG*fU*mA*fC*mU*fC* U.).

10. The method of claim 1 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1313 (mC*mA*mC.mA.mC.mA.mG.mC.mA.mU.mA*mU*mA.TEG-Chl) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1314 (P.mU. A.fU. A.fU. G.fC.fU. G.fU. G.fU.mG*fU*mA*fC*mU*fC* U.).

11. The method of claim 1 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1155 (mU*mC*mA.mU.mC.mA.mG.mU.mG.mU.mU*mA*mA.TEG-Chl) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1156 (P.mU.fU. A. A.fC. A.fC.fU. G. A.fU. G. A* A*fC*fC*mA*mA* G.).

12. The method of claim 1 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1157 (mU*mC*mA.mU.mC.mA.mG.mU.mG.mU.mU*mA*mA.TEG-Chl) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1158 (P.mU.fU. A. A.fC. A.fC.fU. G. A.fU. G.mA*mA*fC*fC*mA*mA* G.).

13. The method of claim 1 , wherein the sd-rxRNA® is hydrophobically modified, optionally wherein the sd-rxRNA® is linked to one or more hydrophobic conjugates, and/or the sd-rxRNA® includes at least one 5-methyl C or U modification.

14. The method of claim 7 , wherein the sense strand of the sd-rxRNA® that is directed against VEGF comprises at least 12 contiguous nucleotides of a sequence selected from the group consisting of: SEQ ID NOs: 1317 (AGAACAGUCCUUA), 1357 (UGCGGAUCAAACA), 1379 (A. G. A. A.mC. A. G.mU.mC.mC.mU.mU. A.Chl), and 1397 (mU. G.mC. G. G. A.mU.mC. A. A. A.mC. A.Chl), and wherein the antisense strand of the sd-rxRNA® that is directed against VEGF comprises at least 12 contiguous nucleotides of a sequence selected from the group consisting of: SEQ ID NOs: 1318 (UAAGGACUGUUCUGUCGAU), 1358 (UGUUUGAUCCGCAUAAUCU), 1380 (P.mU. A. A. G. G. A.fC.fU. G.fU.fU.fC.fU* G*fU*fC* G* A* U), and 1398 (P.mU. G.fU.fU.fU. G. A.fU.fC.fC. G.fC. A*fU* A* A*fU*fC* U).

15. The method of claim 14 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1317 (AGAACAGUCCUUA) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1318 (UAAGGACUGUUCUGUCGAU).

16. The method of claim 14 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1357 (UGCGGAUCAAACA) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1358 (UGUUUGAUCCGCAUAAUCU).

17. The method of claim 14 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1379 (A. G. A. A.mC. A. G.mU.mC.mC.mU.mU. A.Chl) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1380 (P.mU. A. A. G. G. A.fC.fU. G.fU.fU.fC.fU* G*fU*fC* G* A* U).

18. The method of claim 14 , wherein the sense strand of the sd-rxRNA® comprises SEQ ID NO: 1397 (mU. G.mC. G. G. A.mU.mC. A. A. A.mC. A.Chl) and the antisense strand of the sd-rxRNA® comprises SEQ ID NO: 1398 (P.mU. G.fU.fU.fU. G. A.fU.fC.fC. G.fC. A*fU* A* A*fU*fC* U).

19. The method of claim 7 , wherein the sd-rxRNA® is hydrophobically modified, optionally wherein the sd-rxRNA® is linked to one or more hydrophobic conjugates, and/or the sd-rxRNA® includes at least one 5-methyl C or U modification.