COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS
Embodiments of methods of using siRNAs targeting VEGF including an siRNA defined by SEQ ID NO: 77 and SEQ ID NO: 78 to stabilize visual acuity in a subject, to inhibit choroidal neovascularization lesions, to treat age-related macular degeneration, to treat diabetic macular edema, and to decrease foveal thickness in subjects are disclosed. Additionally, methods of treating age-related macular degeneration and diabetic macular edema by administering combinatorial therapy comprising an siRNA targeting VEGF and a non-siRNA VEGF antagonist are described.
1 . A method of stabilizing visual acuity in a subject comprising administering to the subject an effective amount of an siRNA comprising a sense RNA strand of SEQ ID NO: 77 and an antisense RNA strand of SEQ ID NO: 78.
2 . The method of claim 1 , wherein the sense and antisense RNA strands are stabilized against nuclease degradation.
3 . The method of claim 1 , wherein the siRNA is administered by an intraocular administration route.
4 . The method of claim 3 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
5 . The method of claim 1 further comprising administering a VEGF antagonist.
6 . The method of claim 5 , wherein the VEGF antagonist is a monoclonal antibody targeting human VEGF selected from bevacizumab and ranibizumab.
7 . The method of claim 5 , wherein the VEGF antagonist is ranibizumab.
8 . The method of claim 1 , wherein the effective amount is from about 0.5 mg to about 5 mg.
9 . The method of claim 1 , wherein the effective amount is about 2.5 mg.
10 . The method of claim 1 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
11 . The method of claim 1 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
12 . The method of claim 1 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.
13 . A method of inhibiting choroidal neovascularization in a subject comprising administering to the subject an effective amount of an siRNA comprising a sense RNA strand of SEQ ID NO: 77 and an antisense RNA strand of SEQ ID NO: 78.
14 . The method of claim 13 , wherein the sense and antisense RNA strands are stabilized against nuclease degradation.
15 . The method of claim 13 , wherein the siRNA is administered by an intraocular administration route.
16 . The method of claim 15 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
17 . The method of claim 13 further comprising administering a VEGF antagonist.
18 . The method of claim 17 , wherein the VEGF antagonist is a monoclonal antibody targeting human VEGF selected from bevacizumab and ranibizumab.
19 . The method of claim 17 , wherein the VEGF antagonist is ranibizumab.
20 . The method of claim 13 , wherein the effective amount is from about 0.5 mg to about 5 mg.
21 . The method of claim 13 , wherein the effective amount is about 2.5 mg.
22 . The method of claim 13 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
23 . The method of claim 13 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
24 . The method of claim 13 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.
25 . A method of treating diabetic macular edema in a subject comprising administering to the subject an effective amount of an siRNA comprising a sense RNA strand of SEQ ID NO: 77 and an antisense RNA strand of SEQ ID NO: 78.
26 . The method of claim 25 , wherein the sense and antisense RNA strands are stabilized against nuclease degradation.
27 . The method of claim 25 , wherein the siRNA is administered by an intraocular administration route.
28 . The method of claim 27 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
29 . The method of claim 25 further comprising administering a VEGF antagonist.
30 . The method of claim 29 , wherein the VEGF antagonist is a monoclonal antibody targeting human VEGF selected from bevacizumab and ranibizumab.
31 . The method of claim 29 , wherein the VEGF antagonist ranibizumab.
32 . The method of claim 25 , wherein the effective amount is from about 0.5 mg to about 5 mg.
33 . The method of claim 25 , wherein the effective amount is about 2.5 mg.
34 . The method of claim 25 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
35 . The method of claim 25 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
36 . The method of claim 25 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.
37 . A method of decreasing foveal thickness in a subject comprising administering to the subject an effective amount of an siRNA comprising a sense RNA strand of SEQ ID NO: 77 and an antisense RNA strand of SEQ ID NO: 78.
38 . The method of claim 37 , wherein the sense and antisense RNA strands are stabilized against nuclease degradation.
39 . The method of claim 37 , wherein the siRNA is administered by an intraocular administration route.
40 . The method of claim 39 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
41 . The method of claim 37 further comprising administering a VEGF antagonist.
42 . The method of claim 41 , wherein the VEGF antagonist is a monoclonal antibody targeting human VEGF selected from bevacizumab and ranibizumab.
43 . The method of claim 41 , wherein the VEGF antagonist is ranibizumab.
44 . The method of claim 37 , wherein the effective amount is from about 0.5 mg to about 5 mg.
45 . The method of claim 37 wherein the effective amount is about 2.5 mg.
46 . The method of claim 37 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
47 . The method of claim 37 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
48 . The method of claim 37 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.
49 . A method of treating age-related macular degeneration comprising administering to a subject an effective amount of a VEGF antagonist and an effective amount of an siRNA comprising a sense RNA strand and an antisense RNA strand, wherein the sense and the antisense RNA strands form an RNA duplex, and wherein the sense RNA strand comprises a nucleotide sequence identical to a tar-et sequence of about 19 to about 25 contiguous nucleotides in human VEGF mRNA.
50 . The method of claim 49 , wherein the sense RNA strand comprises SEQ ID NO: 77 and the antisense strand comprises SEQ ID NO: 78.
51 . The method of claim 49 , wherein the siRNA is administered by an intraocular administration route.
52 . The method of claim 51 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
53 . The method of claim 49 , wherein the effective amount of said siRNA is from about 0.5 mg to about 5 mg.
54 . The method of claim 49 , wherein the effective amount of said siRNA is about 2.5 mg.
55 . The method of claim 49 , wherein the VEGF antagonist is administered prior to administration of the siRNA.
56 . The method of claim 49 , wherein the VEGF antagonist is administered after administration of the siRNA.
57 . The method of claim 49 , wherein the VEGF antagonist is administered simultaneously with administration of the siRNA.
58 . The method of claim 49 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
59 . The method of claim 49 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
60 . The method of claim 49 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.
61 . The method of claim 49 , wherein said VEGF antagonist is ranibizumab.
62 . The method of claim 61 , wherein said ranibizumab is administered two weeks prior to administration of said siRNA.
63 . The method of claim 62 , wherein said siRNA is administered every four weeks and said ranibizumab is administered ever four weeks on an alternating basis.
64 . The method of claim 63 , wherein said ranibizumab is administered over an eight week period.
65 . The method of claim 64 , wherein said siRNA is administered on a maintenance basis after the eight week period.
66 . The method of claim 49 , wherein said VEGF antagonist is bevacizumab.
67 . The method of claim 49 , wherein said VEGF antagonist is aflibercept.
68 . The method of claim 49 , wherein said VEGF antagonist is pegaptanib.
69 . A method of treating diabetic macular edema comprising administering to a subject an effective amount of a VEGF antagonist and an effective amount of an siRNA comprising a sense RNA strand and an antisense RNA strand, wherein the sense and the antisense RNA strands form an RNA duplex, and wherein the sense RNA strand comprises a nucleotide sequence identical to a target sequence of about 19 to about 25 contiguous nucleotides in human VEGF mRNA.
70 . The method of claim 69 , wherein the siRNA is administered by an intraocular administration route.
71 . The method of claim 70 , wherein the intraocular administration route is selected from intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-corneal and trans-scleral administration.
72 . The method of claim 69 , wherein the effective amount of said siRNA is from about 0.1 mg to about 5 mg.
73 . The method of claim 69 , wherein the effective amount of said siRNA is about 2.5 mg.
74 . The method of claim 69 , wherein the VEGF antagonist is a monoclonal antibody targeting human VEGF selected from bevacizumab and ranibizumab.
75 . The method of claim 69 , wherein the VEGF antagonist is ranibizumab.
76 . The method of claim 69 , wherein the VEGF antagonist is administered prior to administration of the siRNA.
77 . The method of claim 69 , wherein the VEGF antagonist is administered after administration of the siRNA.
78 . The method of claim 69 , wherein the VEGF antagonist is administered simultaneously with administration of the siRNA.
79 . The method of claim 69 , wherein the effective amount of said VEGF siRNA is administered every four weeks.
80 . The method of claim 69 , wherein the effective amount of said VEGF siRNA is administered every eight weeks.
81 . The method of claim 69 , wherein the effective amount of said VEGF siRNA is administered every twelve weeks.