IP Library › Patent Application 14192451
Patent Application
App. No. 14/192,451

RNAi-MEDIATED INHIBITION OF SELECT RECEPTOR TYROSINE KINASES FOR TREATMENT OF PATHOLOGIC OCULAR NEOVASCULARIZATION-RELATED CONDITIONS

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Patent No.
US None
App. No.
14/192,451
Abstract

RNA interference is provided for inhibiton of expression of select receptor tyrosine kinase (RTK) targets in ocular neovascularization-related conditions, including those cellular changes resulting from the signal transduction activity of the select RTK targets that lead directly or indirectly to ocular NV, abnormal angiogenesis, retinal vascular permeability, retinal edema, diabetic retinopathy particularly proliferative diabetic retinopathy, diabetic macular edema, exudative age-related macular degeneration, sequela associated with retinal ischemia, and posterior segment neovascularization.

Claims (35)

1 . A method of treating an ocular neovascularization-related condition in a subject in need thereof, comprising:

administering to an eye of said subject a composition comprising an effective amount of a first and a second interfering RNA and a pharmaceutically acceptable carrier,

wherein each interfering RNA has a length of 19 to 49 nucleotides and comprises a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides; and

wherein said antisense strand of said first interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:1, and

wherein said antisense strand of said second interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, respectively;

wherein said ocular neovascularization-related condition is treated thereby.

2 . The method of claim 1 , wherein said subject is a human.

3 . The method of claim 1 , wherein said antisense strand of said second interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:2 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:2.

4 . The method of claim 1 , wherein said antisense strand of said second interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively.

5 . The method of claim 1 , wherein said antisense strand of said second interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, respectively.

6 . The method of claim 1 , wherein said antisense strand of said first interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:1 comprising nucleotide 922, 942, 990, 1044, 1104, 1169, 1442, 2432, 2742, 2753, 2961, 3065, 3355, 3401, 3414, 3784, 3785, 3825, 4085, 4290, 4356, 4453, 4476, 4515, 4525, 4737, 4863, 4868, 4880, 5042, 5057, 5172, 5650, 5764, 1118, 1609, 1890, 2151, 2323, 2639, or 2654.

7 . The method of claim 1 , wherein said antisense strand of said second interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:2 comprising nucleotide 432, 521, 712, 1273, 1276, 1455, 1467, 1581, 1582, 1809, 1830, 1904, 1905, 1937, 1938, 1945, 2114, 2138, 2153, 2154, 2197, 2199, 2610, 3002, 3165, 3348, 3408, 3410, 3443, 3603, 3624, 3626, 3633, 3645, 3799, 3918, 3974, 4051, 4053, 4110, 923, 1213, 1225, or 1269.

8 . The method of claim 1 , wherein said antisense strand of said second interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:3 comprising nucleotide 489, 537, 574, 613, 1262, 1267, 1268, 1269, 1307, 1315, 1465, 1644, 1976, 2297, 3556, 3842, 4004, 4080, 4257, 4414, 4416, 4430, 4659, 4660, 4692, 4969, 4999, 5000, 5259, 5284, 5341, 5355, 5433, 5750, 6115, 587, 615, 918, 921, 1129, 1478, 2073, 2435, 2436, 2922, 2946, 3203, 3348, 3366, or 3387; or corresponding to SEQ ID NO:4 comprising nucleotide 807, 808, 860, 878, 885, 905, 939, 1065, 1197, 1347, 1692, 2352, 2845, 2958, 3635, 3954, 4162, 4391, 4742, 4774, 4780, 4882, 5183, 5184, 5478, 5480, 5538, 5540, 5542, 5543, 5544, 5546, 5547, 5548, 5562, 5563, 5567, 5591, 5697, 1896, 2193, 2340, 2362, 2363, 2538, 2740, 2747, 2760, 2829, 2926, 3030, 3031, 3192, or 3252.

9 . The method of claim 1 , wherein said antisense strand of said second interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:205 comprising nucleotide 437, 464, 577, 647, 1171, 1198, 1215, 1304, 1305, 1343, 1402, 1460, 1497, 1766, 1767, 2044, 2478, 2560, 2623, 2624, 2779, 2780, 2963, 2990, 3002, 3453, 3615, 3616, 3769, 4064, 4065, 4229, 4465, 4493, 4565, 4708, 5097, 5147, 5372, 5484, 5486, 5487, 5495, 5496, 5568, 5569, or 5726.

10 . The method of claim 1 , further comprising administering to said subject a third interfering RNA having a length of 19 to 49 nucleotides and comprising

a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides;

wherein said antisense strand of said third interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, and said antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively.

11 . The method of claim 1 , further comprising administering to said subject a third interfering RNA having a length of 19 to 49 nucleotides and comprising

a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides;

wherein said antisense strand of said third interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, and said antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, respectively.

12 . The method of claim 1 , further comprising administering to said subject a third interfering RNA having a length of 19 to 49 nucleotides and comprising:

a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides;

wherein said antisense strand of said third interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, and said antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with said hybridizing portion of mRNA corresponding to SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, or SEQ ID NO:210, respectively.

13 . The method of claim 1 , wherein said sense nucleotide strand and said antisense nucleotide strand are connected by a loop nucleotide sequence.

14 . The method of claim 1 , wherein said composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, intracanalicular or suprachoroidal route.

15 . The method of claim 1 , wherein said first interfering RNA is administered via in vivo expression from a first expression vector capable of expressing said first interfering RNA and said second interfering RNA is administered via in vivo expression from a second expression vector capable of expressing said second interfering RNA.

16 . The method of claim 1 , wherein said first interfering RNA is administered via in vivo expression from a first expression vector capable of expressing said first interfering RNA and said second interfering RNA is administered via in vivo expression from a second expression vector capable of expressing said second interfering RNA.

17 . A composition comprising a first and a second interfering RNA, each interfering RNA having a length of 19 to 49 nucleotides, wherein said first interfering RNA comprises a nucleotide sequence of any one of SEQ ID NO:16-SEQ ID NO:49 and SEQ ID NO:164-SEQ ID NO:170, or a complement thereof; and said second interfering RNA comprises a nucleotide sequence of any one of SEQ ID NO:50-SEQ ID NO:89, SEQ ID NO:90-SEQ ID NO:124, SEQ ID NO:125-SEQ ID NO:163, SEQ ID NO:171-SEQ ID NO:174, SEQ ID NO:175-SEQ ID NO:189, SEQ ID NO:190-SEQ ID NO:204, and SEQ ID NO:211-SEQ ID NO:439, or a complement thereof, and a pharmaceutically acceptable carrier.

18 . The composition of claim 17 , wherein said interfering RNA is an shRNA, an siRNA, or an miRNA.

19 . The method of claim 1 , wherein said human has retinal edema, diabetic retinopathy, sequela associated with retinal ischemia, or posterior segment neovascularization.

20 . A method of attenuating expression of an ocular neovascularization-related condition target mRNA first variant without attenuating expression of an ocular neovascularization-related condition target mRNA second variant in a subject, comprising:

administering to said subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, said interfering RNA comprising:

a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, said penultimate 13 nucleotides of said 3′ end of said first variant,

wherein said expression of said first variant mRNA is attenuated without attenuating expression of said second variant mRNA, and wherein said first variant target mRNA is SEQ ID NO:209, and said second variant target mRNA is SEQ ID NO:210.

21 . A composition comprising an interfering RNA having a length of 19 to 49 nucleotides, wherein said interfering RNA comprises a nucleotide sequence that targets any one of SEQ ID NO:16-SEQ ID NO:49, SEQ ID NO:164-SEQ ID NO:170, SEQ ID NO:50-SEQ ID NO:89, SEQ ID NO:90-SEQ ID NO:124, SEQ ID NO:125-SEQ ID NO:163, SEQ ID NO:171-SEQ ID NO:174, SEQ ID NO:175-SEQ ID NO:189, SEQ ID NO:190-SEQ ID NO:204, and SEQ ID NO:211-SEQ ID NO:439, or a complement thereof, and a pharmaceutically acceptable carrier.