US2011028534A1PendingUtilityA1
RNAi INHIBITION OF CTGF FOR TREATMENT OF OCULAR DISORDERS
Est. expiryDec 23, 2024(expired)· nominal 20-yr term from priority
A61P 9/10A61P 27/02A61P 27/06C12N 15/1136A61K 31/713C12N 2310/14A61P 17/02C12N 15/111C12N 2320/32A61K 48/00
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Claims
Abstract
RNA interference is provided for inhibition of connective tissue growth factor mRNA expression in ocular disorders involving CTGF expression. Ocular disorders involving aberrant CTGF expression include glaucoma, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy and wound healing. Such disorders are treated by administering interfering RNAs of the present invention.
Claims
exact text as granted — not AI-modified1 . A method of attenuating expression of connective tissue growth factor mRNA in an eye of a subject, comprising:
administering to the 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 comprising:
a sense nucleotide sequence, an antisense nucleotide sequence, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides;
wherein the antisense sequence 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 the hybridizing portion of mRNA corresponding to SEQ ID NO:1,
wherein the expression of connective tissue growth factor mRNA is attenuated.
2 . The method of claim 1 wherein the subject has a connective tissue growth factor-associated ocular disorder.
3 . The method of claim 1 wherein the subject is at risk of developing a connective tissue growth factor-associated ocular disorder.
4 . The method of claim 2 wherein the connective tissue growth factor-associated ocular disorder is glaucoma, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy or wound healing.
5 . The method of claim 1 wherein the antisense sequence has a region of at least near-perfect contiguous complementarity of at least 21 to 23 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:1 and comprises an additional TT sequence at the 3′ end of each of the sense and the antisense sequence.
6 . The method of claim 1 wherein the sense nucleotide sequence and the antisense nucleotide sequence are connected by a loop nucleotide sequence.
7 . The method of claim 1 wherein the composition is administered via a topical, intravitreal, or transcleral route.
8 . The method of claim 1 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666.
9 . The method of claim 1 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 901, or 1488.
10 . The method of claim 1 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 comprising nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666.
11 . The method of claim 1 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 comprising nucleotide 379, 901, or 1488.
12 . The method of claim 1 wherein the antisense sequence comprises:
3′-TTcccguuuuucacguaggca-5′.
SEQ ID NO: 33
13 . The method of claim 1 wherein the antisense sequence comprises:
3′-TTcccggagaagacacugaag-5′.
SEQ ID NO: 31
14 . The method of claim 1 wherein the antisense sequence comprises:
3′-TTccaaucauaguagucuauc-5′.
SEQ ID NO: 28
15 . The method of claim 1 wherein the interfering RNA comprises:
5′-gggccucuucugugacuucTT-3′
SEQ ID NO: 30
and
3′-TTcccggagaagacacugaag-5′.
SEQ ID NO: 31
16 . The method of claim 1 wherein the interfering RNA comprises:
5′-gggcaaaaagugcauccguTT-3′
SEQ ID NO: 32
and
3′-TTcccguuuuucacguaggca-5′.
SEQ ID NO: 33
17 . The method of claim 1 wherein the interfering RNA comprises:
5′-gguuaguaucaucagauagTT-3′
SEQ ID NO: 27
and
3′-TTccaaucauaguagucuauc-5′.
SEQ ID NO: 28
18 . The method of claim 1 further comprising administering to the eye of the subject a second interfering RNA having a length of 19 to 49 nucleotides, and comprising
a sense nucleotide sequence, an antisense nucleotide sequence, and a region of at least near-perfect complementarity of at least 19 nucleotides;
wherein the antisense sequence of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:1, and the antisense sequence 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:1.
19 . A method of attenuating expression of connective tissue growth factor mRNA in an eye of a subject, comprising:
administering to the eye of the subject a composition comprising an effective amount of single-stranded interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier,
wherein the single stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666, and the interfering RNA has a region of at least near-perfect complementarity with the hybridizing portion of mRNA corresponding to SEQ ID NO:1,
wherein the expression of connective tissue growth factor mRNA is attenuated.
20 . A method of treating a connective tissue growth factor-associated ocular disorder in a subject in need thereof, comprising:
administering to the 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 comprising:
a sense nucleotide sequence, an antisense nucleotide sequence, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides;
wherein the antisense sequence 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 the hybridizing portion of mRNA corresponding to SEQ ID NO:1,
wherein the connective tissue growth factor-associated ocular disorder is treated thereby.
21 . The method of claim 20 wherein the connective tissue growth factor-associated ocular disorder is glaucoma, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy or aberrant wound healing.
22 . The method of claim 20 wherein the antisense sequence has a region of at least near-perfect contiguous complementarity of at least 21 to 23 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:1 and comprises an additional TT sequence at the 3′ end of each of the sense and the antisense sequence.
23 . The method of claim 20 wherein the sense nucleotide sequence and the antisense nucleotide sequence are connected by a loop nucleotide sequence.
24 . The method of claim 20 wherein the composition is administered via a topical, intravitreal, or transcleral route.
25 . The method of claim 20 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666.
26 . The method of claim 20 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 901, or 1488.
27 . The method of claim 20 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 comprising nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666.
28 . The method of claim 20 wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:1 comprising nucleotide 379, 901, or 1488.
29 . The method of claim 20 wherein the antisense sequence comprises:
3′-TTcccguuuuucacguaggca-5′.
SEQ ID NO: 33
30 . The method of claim 20 wherein the antisense sequence comprises:
3′-TTcccggagaagacacugaag-5′.
SEQ ID NO: 31
31 . The method of claim 20 wherein the antisense sequence comprises:
3′-TTccaaucauaguagucuauc-5′.
SEQ ID NO: 28
32 . The method of claim 20 wherein the interfering RNA comprises:
5′-gggccucuucugugacuucTT-3′
SEQ ID NO: 30
and
3′-TTcccggagaagacacugaag-5′.
SEQ ID NO: 31
33 . The method of claim 20 wherein the interfering RNA comprises:
5′-gggcaaaaagugcauccguTT-3′
SEQ ID NO: 32
and
3′-TTcccguuuuucacguaggca-5′.
SEQ ID NO: 33
34 . The method of claim 20 wherein the interfering RNA comprises:
5′-gguuaguaucaucagauagTT-3′
SEQ ID NO: 27
and
3′-TTccaaucauaguagucuauc-5′.
SEQ ID NO: 28
35 . The method of claim 20 further comprising administering to the eye of the subject a second interfering RNA having a length of 19 to 49 nucleotides, and comprising
a sense nucleotide sequence, an antisense nucleotide sequence, and a region of at least near-perfect complementarity of at least 19 nucleotides;
wherein the antisense sequence of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:1, and the antisense sequence 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:1.
36 . A method of treating glaucoma, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy or aberrant wound healing in a subject in need thereof, comprising:
administering to the eye of the subject a composition comprising an effective amount of single-stranded interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier,
wherein the single stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1 beginning at nucleotide 379, 691, 801, 901, 932, 937, 969, 986, 1119, 1170, 1201, 1346, 1473, 1478, 1481, 1488, 1626, 1660, or 1666, and the interfering RNA has a region of at least near-perfect complementarity with the hybridizing portion of mRNA corresponding to SEQ ID NO:1,
wherein the glaucoma, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy or aberrant wound healing is treated thereby.Cited by (0)
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