RNAi-MEDIATED INHIBITION OF STROMAL CELL-DERIVED FACTOR 1-RELATED TARGETS FOR TREATMENT OF NEOVASCULARIZATION-RELATED CONDITIONS
RNA interference is provided for inhibition of stromal cell-derived factor 1 (SDF1)-related targets in pathologic neovascularization-related conditions, including those cellular changes resulting from the signal transduction activity of the SDF1 targets that lead directly or indirectly to ocular neovascularization, 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, for example.
1 . A method of treating a neovascularization-related condition in a subject in need thereof, said method comprising:
administering to an eye of the subject a composition comprising an effective amount of
interfering RNA having a length of 19 to 49 nucleotides, and a pharmaceutically acceptable carrier, wherein
the interfering RNA comprises 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 an mRNA corresponding to any one of SEQ ID NO:6, SEQ ID NO:75-SEQ ID NO:122, and SEQ ID NO: 170-SEQ ID NO: 213;
wherein the neovascularization-related condition is treated thereby.
2 . The method of claim 1 , wherein the interfering RNA comprises a region of at least 14, 15, 16, 17, or 18 contiguous nucleotides having at least 85% sequence complementarity to, or at least 80% sequence identity with, the penultimate 14, 15, 16, 17, or 18 nucleotides of the 3′ end of an mRNA corresponding to any one of SEQ ID NO:6, SEQ ID NO:75-SEQ ID NO:122, and SEQ ID NO: 170-SEQ ID NO: 213.
3 . The method of claim 1 , wherein the composition is administered via an intraocular, or topical route.
4 . The method of claim 1 , wherein the interfering RNA is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.
5 . The method of claim 1 , wherein the interfering RNA is an shRNA, an miRNA, or an siRNA.
6 . The method of claim 1 , wherein the subject is a human and the human has a neovascularization-related condition or is at risk of developing a neovascularization-related condition.
7 . A method of attenuating expression of CXCR4 mRNA in an eye of the subject, comprising:
administering to an eye of 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, said method 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:4 beginning at nucleotide 122, 123, 137, 151, 163, 182, 244, 271, 278, 280, 291, 292, 293, 294, 421, 424, 481, 519, 535, 537, 547, 550, 604, 619, 626, 628, 630, 701, 772, 778, 806, 883, 893, 905, 912, 922, 1063, 1070, 1085, 1088, 1091, 1117, 1122, 1123, 345, 459, 486, 521, 522, 525, 600, 639, 647, 832, 867, 925, 962, 963, 979, 1068, 1190, 1191, 1330, 1448, 1557, 1607, 1609, 1610, 1638, 1652, 1658, 1659, 1661, 1662, 1663, 1664, 1732, 1733, 1756, 1757, 1758, 1759, 1764, 159, 164, or 288, or a portion of mRNA corresponding to SEQ ID NO:5 beginning at nucleotide 106; and
wherein the expression of CXCR4 mRNA is attenuated thereby.
8 . A method of attenuating expression of SDF1 mRNA in an eye of the subject, comprising:
administering to an eye of 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, said method 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:1 beginning at nucleotide 94, 97, 170, 172, 180, 184, 198, 205, 208, 211, 214, 215, 217, 218, 227, 236, 247, 248, 273, 275, 276, 277, 278, 279, 281, 284, 286, 287, 289, 295, 299, 300, 301, 306, 307, 309, 312, 313, 314, 315, 316, 328, 331, 334, 336, 337, 338, 194, 291, 317, 322, 187, 209, 330, 511, 551, 664, 671, 790, 793, 970, 971, 1267, 1301, 1358, 1359, 1388, 1492, 1493, 1495, 1653, 1701, 1708, 1842, 1857, 1858, 1860, 1913, or 1914, or to a portion of mRNA corresponding to SEQ ID NO:2 beginning at nucleotide 494, 495, 598, 996, 997, 999, 1506, 1695, 1783, 1784, 1792, 1862, 1892, 1893, 2081, 2155, 2249, 2284, 3225, 3386, 3400, 3401, or 3431, or to a portion of mRNA corresponding to SEQ ID NO:3 beginning at nucleotide 447, 449, or 450;
wherein the expression of SDF 1 mRNA is attenuated thereby.
9 . The method of claim 7 , wherein the subject is a human and the human has a neovascularization-related condition or is at risk of developing a neovascularization-related condition.
10 . The method of claim 7 , wherein the sense nucleotide strand and the antisense nucleotide strand are connected by a loop nucleotide strand.
11 . The method of claim 7 , wherein the composition is administered via an intraocular or topical route.
12 . The method of claim 7 , wherein the interfering RNA is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.
13 - 22 . (canceled)
23 . A method of treating a neovascularization-related condition in a subject in need thereof, said method comprising:
administering to an eye of the subject a composition comprising a double stranded siRNA
molecule that down regulates expression of a CXCR4 gene via RNA interference,
wherein:
each strand of the siRNA molecule is independently about 19 to about 27 nucleotides in length; and
one strand of the siRNA molecule comprises a nucleotide sequence having substantial complementarity to an mRNA corresponding to the CXCR4 gene so that the siRNA molecule directs cleavage of the mRNA via RNA interference.
24 - 28 . (canceled)
29 . The method of claim 23 , wherein each strand of the siRNA molecule is independently about 19 nucleotides to about 25 nucleotides in length or is independently about 19 nucleotides to about 21 nucleotides in length.
30 - 31 . (canceled)