IP Library › Patent Application 14615144
Patent Application
App. No. 14/615,144

RNAi Inhibition of Serum Amyloid A For Treatment of Glaucoma

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Patent No.
US None
App. No.
14/615,144
Abstract

RNA interference is provided for inhibition of serum amyloid A mRNA expression in glaucomas involving SAA expression.

Claims (141)

1 - 2 . (canceled)

3 . 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 80% contiguous complementarity of at least 19 nucleotides between the sense and antisense sequences; wherein the antisense sequence hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2, and has a region of at least 80% contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2 for use in treating serum amyloid A-associated glaucoma in an eye of a subject.

4 . 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 nucleotide sequence having a region of at least 80% contiguous complementarity of at least 19 nucleotides with a hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2, wherein the nucleotide sequence hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2, for use in treating amyloid A-associated glaucoma in an eye of a subject.

5 . An in vitro method for attenuating expression of serum amyloid A mRNA comprising administering 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 80% contiguous complementarity of at least 19 nucleotides between the sense and antisense sequences; wherein the antisense sequence hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO:2, and has a region of at least 80% contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO:2 to a cell.

6 . An in vitro method for attenuating expression of serum amyloid A mRNA comprising administering an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a nucleotide sequence having a region of at least 80% contiguous complementarity of at least 19 nucleotides with a hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO:2, wherein the nucleotide sequence hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2 to a cell.

7 . The composition of claim 3 , wherein the antisense sequence has a region of at least 80% contiguous complementarity of at least 21 to 23 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2, and comprises an additional TT sequence at the 3 end of each of the sense and the antisense sequence.

8 . The composition of claim 3 , wherein the sense nucleotide sequence and the antisense nucleotide sequence are connected by a loop nucleotide sequence.

9 . The composition claim 3 , wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO: 1 beginning at nucleotide 230, 357, 362, 380, 447, 470, 527, 531, 548, or 557.

10 . The composition of claim 3 , wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO: 2 beginning at nucleotide 43, 170, 175, 193, 260, 283, 339, or 370.

11 . The composition of claim 3 , wherein the antisense sequence is designed to target a nucleotide sequence of mRNA corresponding to SEQ ID NO:2 beginning at nucleotide 252, 271, 276, 325, 343.

12 . The composition of claim 3 , wherein the antisense sequence comprises:

(SEQ ID NO: 37)

CUUUGCCACUCCUGCCCCA,

(SEQ ID NO: 38)

UCGGAAGUGAUUGGGGUCU,

(SEQ ID NO: 39)

UUUGUCUGAGCCGAUGUAA,

(SEQ ID NO: 40)

AACCAGGCCCGUGAGAAGC,

(SEQ ID NO: 41)

CUGAGCCGAUGUAAUUGGC,

(SEQ ID NO: 69)

GCCACUCCUGCCCCAUUUA,

(SEQ ID NO: 42)

CCCCCGAGCAUGGAAGUAU,

(SEQ ID NO: 43)

CUCUGGCAUUGCUGAUCAC,

(SEQ ID NO: 44)

GCCUGUGAGUCUCUGGAUA,

(SEQ ID NO: 45)

GCCACUCCUGCCCCAUUUA,

(SEQ ID NO: 46)

GCCAGCAGGUCGGAAGUGA,

(SEQ ID NO: 47)

AGUCUCUGGAUAUUCUCUC,

(SEQ ID NO: 48)

UUUAUUGGCAGCCUGAUCG,

(SEQ ID NO: 49)

UUGCUGAUCACUUCUGCGG,

(SEQ ID NO: 50)

CUGGAUAUUCUCUCUGGCA,

(SEQ ID NO: 51)

UCUGCCACUCCUGCCCCAU,

(SEQ ID NO: 52)

AACCCCUUGGAGAGCCUCC,

(SEQ ID NO: 53)

UGCCCAUGUCCCCAACCCC,

(SEQ ID NO: 54)

AUAGAGAUAUCUGUUUGAA,

(SEQ ID NO: 55)

CGAGCAUAGAGAUAUGUGU,

(SEQ ID NO: 56)

CUUUGGGCAGCAUCAUAGU,

(SEQ ID NO: 57)

AGACACCCCCAGGUCCUCU,

(SEQ ID NO: 58)

CCUGGAACGGCUGAUGAGU,

(SEQ ID NO: 59)

CCAAAUAAAUAGUAGUCUA,

(SEQ ID NO: 60)

UCCAAUACAGUGCUGCUGU,

(SEQ ID NO: 61)

CUCAGCUUUCUCGUUGGAC,

(SEQ ID NO: 62)

CCAUUCCUCAGCUUUCUCG,

(SEQ ID NO: 63)

CCGGCCCCAUUCCUCAGCU,

(SEQ ID NO: 64)

CUUUGCCACUCCGGCCCCA,

or

(SEQ ID NO: 65)

UCUGAAGCGGUCGGGGUCU,

13 . The composition of claim 4 , wherein the antisense sequence comprises:

(SEQ ID NO: 37)

CUUUGCCACUCCUGCCCCA,

(SEQ ID NO: 38)

UCGGAAGUGAUUGGGGUCU,

(SEQ ID NO: 39)

UUUGUCUGAGCCGAUGUAA,

(SEQ ID NO: 40)

AACCAGGCCCGUGAGAAGC,

(SEQ ID NO: 41)

CUGAGCCGAUGUAAUUGGC,

(SEQ ID NO: 69)

GCCACUCCUGCCCCAUUUA,

(SEQ ID NO: 42)

CCCCCGAGCAUGGAAGUAU,

(SEQ ID NO: 43)

CUCUGGCAUUGCUGAUCAC,

(SEQ ID NO: 44)

GCCUGUGAGUCUCUGGAUA,

(SEQ ID NO: 45)

GCCACUCCUGCCCCAUUUA,

(SEQ ID NO: 46)

GCCAGCAGGUCGGAAGUGA,

(SEQ ID NO: 47)

AGUCUCUGGAUAUUCUCUC,

(SEQ ID NO: 48)

UUUAUUGGCAGCCUGAUCG,

(SEQ ID NO: 49)

UUGCUGAUCACUUCUGCGG,

(SEQ ID NO: 50)

CUGGAUAUUCUCUCUGGCA,

(SEQ ID NO: 51)

UCUGCCACUCCUGCCCCAU,

(SEQ ID NO: 52)

AACCCGUUGGAGAGCCUCC,

(SEQ ID NO: 53)

UGCCCAUGUCCCCAACCCC,

(SEQ ID NO: 54)

AUAGAGAUAUCUGUUUGAA,

(SEQ ID NO: 55)

CGAGCAUAGAGAUAUCUGU,

(SEQ ID NO: 56)

CUUUGGGCAGCAUCAUAGU,

(SEQ ID NO: 57)

AGACACCCCCAGGUCCUCU,

(SEQ ID NO: 58)

CCUGGAACGGCUGAUGAGU,

(SEQ ID NO: 59)

CCAAAUAAAUAGUAGUCUA,

(SEQ ID NO: 60)

UCCAAUACAGUGCUGCUGU,

(SEQ ID NO: 61)

CUCAGCUUUCUCGUUGGAC,

(SEQ ID NO: 62)

CCAUUCCUCAGCUUUCUCG,

(SEQ ID NO: 63)

CCGGCCCCAUUCCUCAGCU,

(SEQ ID NO: 64)

CUUUGCCACUCCGGCCCCA,

or

(SEQ ID NO: 65)

UCUGAAGCGGUCGGGGUCU.

14 . The composition of claim 3 , wherein the interfering RNA comprises a modification on a base portion, on a sugar portion or on a phosphate portion.

15 . The composition of claim 3 , wherein the composition further comprises 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 80% complementarity of at least 19 nucleotides between the sense and antisense sequences; 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 or SEQ ID NO: 2 and the antisense sequence has a region of at least 80% contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2.

16 . The composition of claim 3 , wherein the composition comprises an effective amount of a mixture of at least four interfering RNAs, each interfering RNA having a length of 19 to 49 nucleotides, and a pharmaceutically acceptable carrier, each interfering RNA comprising: a sense nucleotide sequence, an antisense nucleotide sequence, and a region of at least 80% contiguous complementarity of at least 19 nucleotides between the sense and antisense sequences of each of the four interfering RNAs; wherein the antisense sequences of the mixture hybridize under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 2 beginning at nucleotide 175, 252, 276, and 325, respectively, and have a region of at least 80% contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO: 2 beginning at nucleotide 175, 252, 276, and 325, respectively.

17 . The composition of claim 4 , wherein the composition further comprises a second interfering RNA having a length of 19 to 49 nucleotides, and comprising a second nucleotide sequence having a region of at least 80% contiguous complementarity of at least 19 nucleotides with a second hybridizing portion of mRNA corresponding to SEQ ID NO: 1 or SEQ ID NO: 2.

18 . The composition of claim 4 , wherein the composition comprises an effective amount of a mixture of at least four interfering RNAs, each interfering RNA having a length of 19 to 49 nucleotides, and the mixture comprising: a first, second, third and fourth nucleotide sequence having a region of at least 80% contiguous complementarity of at least 19 nucleotides with the hybridizing portion of rnRNA corresponding to SEQ ID NO: 2 beginning at nucleotide 175, 252, 276, and 325, respectively.

19 . The composition of claim 3 , wherein the composition is prepared for administration via a topical, intravitreal, or transcleral route.

20 . The composition of claim 4 , wherein the composition is prepared for administration via a topical, intravitreal, or transcleral route.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 11, 2015
From: NOVARTIS AG
To: ARROWHEAD RESEARCH CORPORATION
Reel/Frame 035604/0484 →