US2011124708A1PendingUtilityA1

Rnai-mediated inhibition of ocular hypertension targets

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Assignee: ALCON INCPriority: Feb 1, 2005Filed: Dec 14, 2010Published: May 26, 2011
Est. expiryFeb 1, 2025(expired)· nominal 20-yr term from priority
Inventors:Allan R. ShepardJon E. ChattertonAbbot F. Clark
A61P 43/00A61P 9/12A61P 27/06C12N 2310/14C12Y 301/01007C12Y 306/03009C12N 15/1138A61P 27/02C12N 15/1137C12N 2310/111C12N 2310/53C12Y 402/01001A61K 31/713C12N 15/113
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Claims

Abstract

RNA interference is provided for inhibition of ocular hypertension target mRNA expression for lowering elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Ocular hypertension targets include carbonic anhydrase II, IV, and XII; β1- and β2 adrenergic receptors; acetylcholinesterase; Na + /K + -ATPase; and Na—K-2Cl cotransporter. Ocular hypertension is treated by administering interfering RNAs of the present invention.

Claims

exact text as granted — not AI-modified
1 . A method of attenuating expression of an ocular hypertension target mRNA of a subject, comprising:
 administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising:
 a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides; 
 wherein the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively, 
   wherein the expression of an ocular hypertension target mRNA is attenuated.   
     
     
         2 . The method of  claim 1  wherein the subject is a human and the human has ocular hypertension. 
     
     
         3 . The method of  claim 1  wherein the subject is a human and the human is at risk of developing ocular hypertension. 
     
     
         4 . The method of  claim 1  wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route. 
     
     
         5 . The method of  claim 1  wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA. 
     
     
         6 . The method of  claim 1  wherein the ocular hypertension target mRNA encodes a β1- or β2-adrenergic receptor, and the antisense strand 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 the hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively. 
     
     
         7 . The method of  claim 1  wherein the ocular hypertension target mRNA encodes an acetylcholinesterase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123, respectively. 
     
     
         8 . The method of  claim 1  wherein the ocular hypertension target mRNA encodes a subunit of Na + /K + -ATPase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132, respectively. 
     
     
         9 . The method of  claim 1  wherein the ocular hypertension target mRNA encodes a Na—K-2Cl cotransporter, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133, respectively. 
     
     
         10 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:3 comprising nucleotide 468, 523, 799, 1563, 1565, 1569, 1593, 1613, 1614, 1626, 310, 322, 726, 769, 772, 801, 802, 1501, 1576, 1577, 1579, 1580, 1581, 1586, 1590, 1592, 1594, 1615, 1616, 1632, 1633, or 1654. 
     
     
         11 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:4 comprising nucleotide 329, 375, 1031, 1046, 1149, 1163, 1371, 1401, 1426, 1880, 283, 607, 608, 609, 619, 623, 722, 857, 1037, 1091, 1115, 1124, 1136, 1137, 1151, 1164, 1393, 1394, 1395, 1406, 1407, 1427, 1428, 1429, 1442, 1725, 1726, 1756, 1757, 1758, 1767, 1790, 1791, 1792, 1793, 1803, 1861, 1869, 1971, 1972, or 1979. 
     
     
         12 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:123 comprising nucleotide 1875, 1890, 1891, 2011, 2012, 2133, or 2134. 
     
     
         13 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:5 comprising nucleotide 366, 370, 384, 385, 525, 588, 768, 1045, 1046, 1061, 1090, 1232, 1314, 1316, 1460, 1461, 1462, 1528, 1607, 1705, 1713, 382, 393, 397, 622, 1131, 1459, 1530, 2251, 2885, 2886, 386, 1231, 1315, 2047, 2049, 2053, 2055, 2057, 2125, 2126, 2127, 2250, 2253, 2258, 2260, 2318, 2395, 2397, 2404, 2405, 2643, 2645, or 2887. 
     
     
         14 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:124 comprising nucleotide 2208, 2275, 2307, 2526, 2538, 2592, 2628, 2979, 2985, 3093, 3474, 3504, 3505, 3506, 3518, 343, 442, 700, 707, 811, 907, 1059, 1363, 1594, 1662, 1758, 1760, 1896, 2037, or 2147. 
     
     
         15 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:125 comprising nucleotide 436, 441, 443, 552, 617, 701, 702, 832, 2204, 2291, or 2495. 
     
     
         16 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:6 comprising nucleotide 471, 1990, 3080, 3797, 4037, 4093, 4225, 4323, 5213, 5285, 214, 467, 470, 472, 473, 632, 825, 946, 1693, 1767, 1768, 2157, 2263, 2589, 2590, 2765, 2988, 3094, 3144, 3145, 3344, 3345, 3418, 3666, 3828, 3850, 4040, 4041, 4061, 4882, 4894, 4900, 5040, 5114, 5115, 5128, 5129, 5253, 5296, 5375, 5384, or 5385. 
     
     
         17 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:126 comprising nucleotide 240, 272, 362, 1836, 1851, 2103, 2137, 2138, 2139, 2157, 2158, 2160, 2425, 2580, 2601, 2646, 2650, 2794, 2803, 3116, 3124, 3126, 3129, or 3377. 
     
     
         18 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:127 comprising nucleotide 113, 612, 702, 833, 1101, 1732, 1733, 1836, 2070, 2071, 2143, 2328, 2475, 2861, 2862, 2952, 3203, 3281, 3377, 3379, 3470, 3471, 3554, 3614, 3615, 3616, 3617, 3625, 3626, 3642, 3646, 3647, 3653, 3655, 3797, 3801, 3803, 3809 or 3810. 
     
     
         19 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:128 comprising nucleotide 126, 251, 252, 253, 331, 427, 429, 520, 521, 530, 601, 602, 603, 604, 664, 665, 666, 667, 675, 676, 692, 696, 697, 702, 703, 705, 707, 847, 851, 853, 859, or 860. 
     
     
         20 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:129 comprising nucleotide 1096, 1099, 1130, 1131, 1167, 1299, 1441, 1450, 1451, 1452, 1564, 1746, 1750, 1751, 1752, 1795, 203, 204, 214, 222, 224, 225, 226, 380, 525, 591, 612, 613, 615, 635, 636, 663, 664, 669, 699, 765, 790, 839, 840, 841, 900, 909, 933, or 947. 
     
     
         21 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:130 comprising nucleotide 1063, 1102, 1106, 1107, 1108, 1109, 1111, or 1151. 
     
     
         22 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:131 comprising nucleotide 653, 654, 771, 773, 841, 849, 853, 917, 918, 926, 927, 931, 981, 983, 984, 996, 998, 1022, 1023, 1160, 1214, 1355, 1356, 1381, 1394, 1425, 1474, 1550, 1620, 1707, 1740, 1753, 1825, 1956, 1965, 2598, 2599, 2608, 2828, 2829, 2888, 3012, or 3251. 
     
     
         23 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:132 comprising nucleotide 292, 434, 438, 457, 459, 488, 490, 498, 499, 592, 639, 723, 774, 775, 788, 857, 858, 910, 911, 930, 931, 932, 1009, 1010, 1023, 1024, 1111, 1146, 1147, 1220, 1246, 1321, 1325, 1326, 1327, 1331, 1437, 1548, 1571, 1785, 1786, or 1787. 
     
     
         24 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:7 comprising nucleotide 675, 974, 1373, 1780, 2102, 2151, 2315, 2542, 2609, 3197, 67, 71, 73, 353, 405, 864, 911, 912, 913, 1409, 1748, 1811, 1935, 1937, 1993, 2012, 2346, 2388, 2437, 2586, 3007, 3008, 3022, 3130, 3210, 3237, or 3271. 
     
     
         25 . The method of  claim 1  wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:133 comprising nucleotide 748, 749, 753, 1119, 1169, 1499, 1509, 1820, 2081, 2118, 2147, 2615, 2644, 2659, 2663, 2671, 2672, 2793, 2812, 2914, 2948, 3044, 3334, 3391, 3480, 3520, 3549, 3639, 3840, 3941, 3944, 4001, 4995, 4997, 5141, 5143, 5249, 5375, 5834, 5852, 5981, or 6678. 
     
     
         26 . The method of  claim 1  further comprising administering to the subject a second 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 the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively.

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