US2016257962A1PendingUtilityA1
Rna interference mediated inhibition of isocitrate dehydrogenase (idh1) gene expression
Est. expiryJun 6, 2031(~4.9 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 43/00C12N 2310/332C12N 15/1137C07H 21/02C12N 2310/315C12N 2310/3533C12N 2310/321C12N 2310/14C12N 2310/317C12Y 101/01042C12N 2310/3521
44
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Claims
Abstract
The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of IDH1 and mutant IDH1 gene expression and/or activity, and/or modulate an IDH1 or mutant IDH1 gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules, including small nucleic acid molecules such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules, that are capable of mediating or that mediate RNA interference (RNAi) against IDH1 or mutant IDH1 gene expression.
Claims
exact text as granted — not AI-modified1 .- 40 . (canceled)
41 . An isolated double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of IDH1 or mutant IDH1, wherein:
(a) the siNA comprises a sense strand and an antisense strand; (b) each strand is independently 15 to 30 nucleotides in length; and, (c) at least one strand comprises at least a 15 nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-506.
42 . A double-stranded siNA molecule of claim 1 , wherein:
the antisense strand comprises at least 15 nucleotides having sequence complementary to any of:
(SEQ ID NO: 7)
5′-CUAUCAUCAUAGGUCGUCA-3′;
(SEQ ID NO: 11)
5′-CAUCAUAGGUCGUCAUGCU-3′;
(SEQ ID NO: 12)
5′-AUCAUAGGUCGUCAUGCUU-3′;
(SEQ ID NO: 13)
5′-UCAUAGGUCGUCAUGCUUA-3′;
(SEQ ID NO: 38)
5′-CAUCAUAGGUUGUCAUGCU-3′;
(SEQ ID NO: 39)
5′-AUCAUAGGUUGUCAUGCUU-3′;
(SEQ ID NO: 40)
5′-UCAUAGGUUGUCAUGCUUA-3′;
(SEQ ID NO: 41)
5′-CAUAGGUUGUCAUGCUUAU-3′;
(SEQ ID NO: 59)
5′-CAUAGGUCAUCAUGCUUAU-3′;
or,
(SEQ ID NO: 63)
5′-GGUCAUCAUGCUUAUGGGG-3′.
43 . A double-stranded siNA molecule of claim 41 , wherein the siNA comprises any of:
(SEQ ID NO: 7)
5′-CUAUCAUCAUAGGUCGUCA-3′
and
SEQ ID NO: 446)
5′-UGACGACCUAUGAUGAUAG-3′;
(SEQ ID NO: 11)
5′-CAUCAUAGGUCGUCAUGCU-3′
and
(SEQ ID NO: 450)
5′-AGCAUGACGACCUAUGAUG-3′;
(SEQ ID NO: 12)
5′-AUCAUAGGUCGUCAUGCUU-3′
and
(SEQ ID NO: 451)
5′-AAGCAUGACGACCUAUGAU-3′;
(SEQ IN NO: 13)
5′-UCAUAGGUCGUCAUGCUUA-3′
and
(SEQ ID NO: 452)
5′-UAAGCAUGACGACCUAUGA-3′;
(SEQ ID NO: 38)
5′-CAUCAUAGGUUGUCAUGCU-3′
and
(SEQ ID NO: 477)
5′-AGCAUGACAACCUAUGAUG-3 ′;
(SEQ ID NO: 39)
5′-AUCAUAGGUUGUCAUGCUU-3′
and
(SEQ ID NO: 478)
5′-AAGCAUGACAACCUAUGAU-3′;
(SEQ ID NO: 40)
5′-UCAUAGGUUGUCAUGCUUA-3′
and
(SEQ ID NO: 479)
5′-UAAGCAUGACAACCUAUGA-3′;
(SEQ ID NO: 41)
5′-CAUAGGUUGUCAUGCUUAU-3′
and
(SEQ ID NO: 480)
5′-AUAAGCAUGACAACCUAUG-3 ′;
(SEQ ID NO: 59)
5′-CAUAGGUCAUCAUGCUUAU-3′
and
(SEQ ID NO: 498)
5′-AUAAGCAUGAUGACCUAUG-;
or,
(SEQ ID NO: 63)
5′-GGUCAUCAUGCUUAUGGGG-3′
and
(SEQ ID NO: 502)
5′-CCCCAUAAGCAUGAUGACC-3′.
44 . A double-stranded siNA molecule of claim 41 , wherein at least one nucleotide is a chemically modified nucleotide.
45 . A double-stranded siNA molecule of claim 41 comprising at least one phosphorothioate internucleotide linkage.
46 . A double-stranded siNA molecule of claim 41 comprising a cap on the 3′-end, 5′-end, or both 3′ and 5′ ends of at least one strand.
47 . A double-stranded siNA molecule of claim 41 comprising one or more 3′-overhang nucleotides on one or both strands.
48 . A double-stranded siNA molecule of claim 41 , wherein the 5′-end of the antisense strand is phosphorylated.
49 . A double-stranded siNA molecule of claim 47 , wherein the 3′-overhang nucleotides on at least one strand are 2′-O-methyl nucleotides.
50 . A double-stranded siNA molecule of claim 44 , wherein the at least one chemically modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide.
51 . A double-stranded siNA molecule of claim 44 , wherein the at least one chemically modified nucleotide is a 2′-deoxy nucleotide.
52 . A double-stranded siNA molecule of claim 44 , wherein the at least one chemically modified nucleotide is a 2′-O-alkyl nucleotide.
53 . A double-stranded short interfering nucleic acid (siNA) molecule, comprising formula (A) having a sense strand and an antisense strand:
wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid molecule; wherein the antisense strand comprises at least a 15 nucleotide sequence of SEQ ID NO: 446, SEQ ID NO: 450, SEQ ID NO: 451, SEQ ID NO: 452, SEQ ID NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID NO: 480, SEQ ID NO: 498, or SEQ ID NO: 502; and the sense strand comprises a sequence having complementarity to the antisense strand;
each N is independently either a nucleotide that is unmodified or chemically modified, or a non-nucleotide;
each B is a terminal cap that is present or absent;
(N) represents overhanging nucleotides, each of which is independently unmodified or chemically modified; X1 and X2 are independently integers from 0 to 4;
X3 is an integer from 15 to 30;
X4 is an integer from 12 to 27; and,
[N1]-[N2]-[N3] are modified nucleotides or ribonucleotides, and wherein [N1]-[N2]-[N3] is selected from the groups consisting of:
(a) [N1] is a 2′-deoxy-2′-fluoro nucleotide, [N2] is a 2′-deoxy-2′-fluoro nucleotide, and [N3] is a 2′-deoxy-2′-fluoro nucleotide;
(b) [N1] is a 2′-deoxy-2′-fluoro nucleotide, [N2] is a 2′-deoxy-2′-fluoro nucleotide, and [N3] is a 2′-deoxy nucleotide;
(c) [N1] is a 2′-deoxy nucleotide, [N2] is a 2′-deoxy-2′-fluoro nucleotide, and [N3] is a 2′-O-methyl nucleotide;
(d) [N1] is a 2′-deoxy nucleotide, [N2] is a 2′-deoxy-2′-fluoro nucleotide, and [N3] is a 2′-deoxy nucleotide; and,
(e) [N1] is a ribonucleotide, [N2] is a ribonucleotide, and [N3] is a ribonucleotide.
54 . A double-stranded siNA molecule according to claim 53 , wherein:
(a) one or more pyrimidine nucleotides in N X4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof; (b) one or more purine nucleotides in N X4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof; (c) one or more pyrimidine nucleotides in N X3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof and, (d) one or more purine nucleotides in N X3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof.
55 . A double-stranded siNA molecule according to claim 53 , wherein X1 is 2 and X2 is 2.
56 . A double-stranded siNA molecule according to claim 53 , wherein each X1 and X2=1 or 2; X3=18, 19, 20, 21, 22, 23 or 24; and, X4=15, 16, 17, 18, 19, 20, or 21.
57 . A double-stranded siNA molecule according to claim 53 , comprising one or more phosphorothioate internucleotide linkages.
58 . A composition comprising a double-stranded siNA molecule of claim 41 in a pharmaceutically acceptable carrier or diluent.
59 . A method of treating a human subject suffering from a condition that is mediated by the action or loss of action of IDH1 or mutant IDH1, which comprises administering to said subject an effective amount of:
(a) a double-stranded siNA molecule according to claim 41 ; or, (b) a composition according to claim 58 .
60 . The method according to claim 59 , wherein the condition is cancer.Join the waitlist — get patent alerts
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