RNAi-MEDIATED INHIBITION OF AQUAPORIN 4 FOR TREATMENT OF IOP-RELATED CONDITIONS
RNA interference is provided for inhibition of aquaporin 4 (AQP4) in intraocular pressure-related conditions, including ocular hypertension and glaucoma such as normal tension glaucoma and open angle glaucoma.
1 . A method of attenuating expression of an AQP4 mRNA in an eye of a patient, comprising administering to the eye of the patient an interfering RNA molecule that down regulates expression of the AQP4 mRNA via RNA interference.
2 . The method of claim 1 , wherein the interfering RNA molecule is double stranded and each strand is independently about 19 to about 27 nucleotides in length.
3 . The method of claim 2 , wherein each strand is independently about 19 nucleotides to about 25 nucleotides in length.
4 . The method of claim 2 , wherein each strand is independently about 19 nucleotides to about 21 nucleotides in length.
5 . The method of claim 2 , wherein the interfering RNA molecule has blunt ends.
6 . The method of claim 2 , wherein the interfering RNA molecule comprises at least one modification.
7 . The method of claim 2 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA.
8 . The method of claim 2 , wherein at least one strand of the interfering RNA molecule comprises a 3′ overhang.
9 . The method of claim 8 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides.
10 . The method of claim 9 , wherein the 3′ overhang comprises 2 nucleotides.
11 . The method of claim 2 , wherein the interfering RNA molecule recognizes a portion of AQP4 mRNA that corresponds to any of SEQ ID NO: 3, and SEQ ID NO: 14-SEQ ID NO: 112.
12 . The method of claim 2 , wherein the interfering RNA molecule recognizes a portion of AQP4 mRNA, wherein the portion comprises nucleotide 113, 319, 398, 447, 516, 533, 541, 542, 544, 550, 581, 582, 596, 603, 618, 652, 802, 848, 849, 908, 917, 926, 927, 929, 953, 1014, 1313, 1782, 2245, 2421, 2433, 2491, 2732, 2955, 2956, 2957, 3089, 3090, 3091, 3324, 3460, 3953, 4194, 4238, 4260, 4265, 4285, 4341, 4342, 4711, 4719, 4721, 5043, 5142, 5145, 1015, 146, 152, 167, 168, 170, 179, 234, 308, 316, 348, 380, 386, 438, 560, 612, 623, 624, 629, 630, 651, 661, 722, 724, 729, 730, 736, 742, 743, 751, 794, 877, 887, 890, 893, 906, 928, 951, 982, 983, 990, 998, 1002, 1010, or 1017 of SEQ ID NO: 1.
13 . The method of claim 2 , wherein the patient has or is at risk of developing an IOP-related condition.
14 . The method of claim 13 , wherein the IOP-related condition is glaucoma.
15 . An interfering RNA molecule having a length of about 19 to about 49 nucleotides, the interfering RNA molecule comprising:
(a) a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′ end of a mRNA corresponding to any one of SEQ ID NO: 3, and SEQ ID NO: 14-SEQ ID NO: 112;
(b) a region of at least 14 contiguous nucleotides having at least 85% sequence complementarity to, or at least 85% sequence identity with, the penultimate 14 nucleotides of the 3′ end of an mRNA corresponding to any one of SEQ ID NO: 3, and SEQ ID NO: 14-SEQ ID NO: 112; or
(c) a region of at least 15, 16, 17, or 18 contiguous nucleotides having at least 80% sequence complementarity to, or at least 80% sequence identity with, the penultimate 15, 16, 17, or 18 nucleotides, respectively, of the 3′ end of an mRNA corresponding to any one of SEQ ID NO: 3, and SEQ ID NO: 14-SEQ ID NO: 112.
16 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule recognizes a portion of AQP4 mRNA that corresponds to any of SEQ ID NO: 3, and SEQ ID NO: 14-SEQ ID NO: 112.
17 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule recognizes a portion of AQP4 mRNA, wherein the portion comprises nucleotide 1113, 319, 398, 447, 516, 533, 541, 542, 544, 550, 581, 582, 596, 603, 618, 652, 802, 848, 849, 908, 917, 926, 927, 929, 953, 1014, 1313, 1782, 2245, 2421, 2433, 2491, 2732, 2955, 2956, 2957, 3089, 3090, 3091, 3324, 3460, 3953, 4194, 4238, 4260, 4265, 4285, 4341, 4342, 4711, 4719, 4721, 5043, 5142, 5145, 1015, 146, 152, 167, 168, 170, 179, 234, 308, 316, 348, 380, 386, 438, 560, 612, 623, 624, 629, 630, 651, 661, 722, 724, 729, 730, 736, 742, 743, 751, 794, 877, 887, 890, 893, 906, 928, 951, 982, 983, 990, 998, 1002, 1010, or 1017 of SEQ ID NO: 1.
18 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA.
19 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule comprises at least one modification.
20 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule is double stranded, and wherein at least one strand of the interfering RNA molecule comprises a 3′ overhang.
21 . The interfering RNA molecule of claim 20 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides.
22 . The interfering RNA molecule of claim 21 , wherein the 3′ overhang comprises 2 nucleotides.
23 . The interfering RNA molecule of claim 15 , wherein the interfering RNA molecule is double stranded, and the interfering RNA molecule has blunt ends.
24 . A composition comprising a combination of an interfering RNA molecule that down regulates expression of the AQP4 mRNA via RNA interference and an interfering RNA molecule that down regulates expression of the AQP1 mRNA via RNA interference.
25 . A method of treating an IOP-related condition in a subject in need thereof, comprising administering to the subject a composition comprising a combination of an interfering RNA molecule that down regulates expression of the AQP4 mRNA via RNA interference and an interfering RNA molecule that down regulates expression of the AQP1 mRNA via RNA interference, wherein the IOP-related condition is treated thereby.