US2017016000A1PendingUtilityA1
Compositions and agents against hepatitis b virus and uses thereof
Est. expiryJul 17, 2035(~9 yrs left)· nominal 20-yr term from priority
A61P 31/20A61P 1/16C12N 2310/14C12N 2310/344C12N 2310/323C12N 15/1131C12N 2310/11
43
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Claims
Abstract
This invention encompasses compounds and compositions useful in methods for medical therapy, in general, for inhibiting Hepatitis B virus in a subject. The compounds have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, and the compounds are targeted to a sequence of an HBV genome.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound comprising a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the compound has a duplex region of from 14 to 29 contiguous monomers in length, wherein the first strand is a passenger strand for RNA interference and the second strand is a guide strand for RNA interference, and wherein the compound comprises a sequence of bases targeted to inhibit expression of an HBV genome.
2 . The compound of claim 1 , wherein the compound contains one to seven UNA monomers.
3 . The compound of claim 1 , wherein the compound contains a UNA monomer at the 1-end (5′ end for non-UNA) of the first strand, a UNA monomer at the 3-end (3′ end for non-UNA) of the first strand, and a UNA monomer at the second position from the 5′ end of the second strand.
4 . The compound of claim 1 , wherein the compound contains a UNA monomer at any one or more of positions 2 to 8 from the 5′ end of the second strand.
5 . The compound of claim 1 , wherein the sequence of bases is selected from the sense, antisense or sense-antisense pairs of the following, and substituted forms thereof:
SEQ
SEQ
REF
NO
ID
POS
ID
Sense (5′-3′)
NO
Antisense (5′-3′)
1578
867
UGUGCACUUCGCUUCACCU
908
AGGUGAAGCGAAGUGCACA
1777
875
GAGGCUGUAGGCAUAAAUU
916
AAUUUAUGCCUACAGCCUC
1581
869
GCACUUCGCUUCACCUCUG
910
CAGAGGUGAAGCGAAGUGC
380
887
UGUCUGCGGCGUUUUAUCA
928
UGAUAAAACGCCGCAGACA
1576
899
CGUGUGCACUUCGCUUCAC
940
GUGAAGCGAAGUGCACACG
1780
877
GCUGUAGGCAUAAAUUGGU
918
ACCAAUUUAUGCCUACAGC
1781
878
CUGUAGGCAUAAAUUGGUC
919
GACCAAUUUAUGCCUACAG
1782
879
UGUAGGCAUAAAUUGGUCU
920
AGACCAAUUUAUGCCUACA
376
885
GAUGUGUCUGCGGCGUUUU
926
AAAACGCCGCAGACACAUC
378
886
UGUGUCUGCGGCGUUUUAU
927
AUAAAACGCCGCAGACACA
411
893
UCCUGCUGCUAUGCCUCAU
934
AUGAGGCAUAGCAGCAGGA
413
895
CUGCUGCUAUGCCUCAUCU
936
AGAUGAGGCAUAGCAGCAG
1580
900
UGCACUUCGCUUCACCUCU
941
AGAGGUGAAGCGAAGUGCA
1581
869
GCACUUCGCUUCACCUCUG
910
CAGAGGUGAAGCGAAGUGC
1575
865
CCGUGUGCACUUCGCUUCA
906
UGAAGCGAAGUGCACACGG
1818
888
AACUUUUUCACCUCUGCCU
929
AGGCAGAGGUGAAAAAGUU
6 . The compound of claim 1 , wherein the compound comprises one of the following pairs:
SEQ ID NO:987 and 988; SEQ ID NO:993 and 994; SEQ ID NO:999 and 1000; SEQ ID NO:1005 and 1006; SEQ ID NO:1009 and 1010; SEQ ID NO:1011 and 1012; SEQ ID NO:1013 and 1014; SEQ ID NO:1015 and 1016; SEQ ID NO:969 and 970; SEQ ID NO:971 and 972; SEQ ID NO:973 and 974; SEQ ID NO:977 and 978; SEQ ID NO:981 and 982; SEQ ID NO:989 and 990; SEQ ID NO:997 and 998; and SEQ ID NO:999 and 1000.
7 . The compound of claim 1 , wherein the compound comprises one of the following pairs:
SEQ ID NO:1145 and 1146; SEQ ID NO:1175 and 1176; SEQ ID NO:1149 and 1150; SEQ ID NO:1163 and 1164; SEQ ID NO:1165 and 1166; SEQ ID NO:1167 and 1168; SEQ ID NO:1169 and 1170; SEQ ID NO:1153 and 1154; SEQ ID NO:1155 and 1156; SEQ ID NO:1157 and 1158; SEQ ID NO:1160 and 1161; SEQ ID NO:1159 and 1160; SEQ ID NO:1147 and 1148; and SEQ ID NO:1151 and 1152.
8 . The compound of claim 1 , wherein the compound has a 3′ overhang comprising one or more UNA monomers, natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides, and combinations thereof.
9 . The compound of claim 1 , wherein the compound has a 3′ overhang comprising one or more deoxythymidine nucleotides, 2′-O-methyl nucleotides, inverted abasic monomers, inverted thymidine monomers, L-thymidine monomers, or glyceryl nucleotides.
10 . The compound of claim 1 , wherein one or more of the nucleic acid monomers is a non-natural nucleotide, a modified nucleotide, or a chemically-modified nucleotide.
11 . The compound of claim 1 , wherein each nucleic acid monomer has a 2′-O-methyl group.
12 . The compound of claim 1 , wherein the compound contains from one to eight nucleic acid monomers modified with a 2′-O-methyl group in the first strand and from one to eleven nucleic acid monomers modified with a 2′-O-methyl group in the second strand.
13 . The compound of claim 1 , wherein the compound contains one or more 2′-methoxyethoxy nucleotides.
14 . The compound of claim 1 , wherein the compound contains one or more 2′-deoxy-2′-fluoro ribonucleotides.
15 . The compound of claim 1 , wherein the compound does not contain fluorine.
16 . The compound of claim 1 , wherein one or more of three monomers at each end of each strand is connected by a phosphorothioate, a chiral phosphorothioate, or a phosphorodithioate linkage.
17 . The compound of claim 1 , wherein the compound has one phosphorothioate linkage between two monomers at the 5′ end of the first strand, one phosphorothioate linkage between two monomers at the 3′ end of the first strand, one phosphorothioate linkage between monomers at the second and third positions from the 3′ end of the first strand, and one phosphorothioate linkage between two monomers at the 3′ end of the second strand.
18 . The compound of claim 1 , wherein the compound is conjugated to a delivery moiety.
19 . The compound of claim 1 , wherein the compound is conjugated to a delivery moiety that binds to a glycoprotein receptor.
20 . The compound of claim 1 , wherein the compound is conjugated to a delivery moiety that binds to a glycoprotein receptor, wherein the delivery moiety comprises a galactose, a galactosamine, or a N-acetylgalactosamine.
21 . The compound of claim 1 , wherein the compound is conjugated to a GalNAc delivery moiety.
22 . The compound of claim 1 , wherein the compound is conjugated to a cholesterol delivery moiety.
23 . The compound of claim 1 , wherein the compound is conjugated to a delivery moiety at an end of the compound and has increased uptake in the liver as compared to an unconjugated compound.
24 . A lipid nanoparticle-oligomer compound comprising one or more compounds of claim 1 attached to the lipid nanoparticle.
25 . A composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.
26 . The composition of claim 25 , wherein the carrier comprises lipid nanoparticles or liposomes.
27 . A composition comprising a first compound of claim 1 targeted to a conserved region of HBV transcripts for genes X, C, P and S, a second compound of claim 1 targeted to inhibit HBsAg, a third compound of claim 1 targeted to a conserved region of HBV transcripts for genes X, C and S, and a pharmaceutically acceptable carrier.
28 . The composition of claim 27 , wherein the carrier comprises lipid nanoparticles or liposomes.
29 . A composition comprising one or more compounds having reference positions from any of positions 1525 to 1582, 374 to 414, 1776 to 1782, 244 to 256, and 1818 to 1866.
30 . The composition of claim 29 , comprising a compound having a reference position from 1525 to 1582, a compound having a reference position from 374 to 414, and a compound having a reference position from 1776 to 1782.
31 . A composition comprising a triad of compounds, wherein the triad is selected from the following:
the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:899 and 940, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:865 and 906, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:869 and 910, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:885 and 926, and the third compound comprises SEQ ID NO:875 and 916; and the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:877 and 918.
32 . An siRNA comprising nucleotides, wherein the siRNA is targeted to HBV and has a sequence selected from the sense, antisense or sense-antisense pairs of the following, and substituted forms thereof:
SEQ
SEQ
REF
ID
ID
POS
NO
Sense (5′-3′)
NO
Antisense (5′-3′)
1777
875
GAGGCUGUAGGCAUAAAUU
916
AAUUUAUGCCUACAGCCUC
1581
869
GCACUUCGCUUCACCUCUG
910
CAGAGGUGAAGCGAAGUGC
380
887
UGUCUGCGGCGUUUUAUCA
928
UGAUAAAACGCCGCAGACA
1576
899
CGUGUGCACUUCGCUUCAC
940
GUGAAGCGAAGUGCACACG
1780
877
GCUGUAGGCAUAAAUUGGU
918
ACCAAUUUAUGCCUACAGC
1781
878
CUGUAGGCAUAAAUUGGUC
919
GACCAAUUUAUGCCUACAG
1782
879
UGUAGGCAUAAAUUGGUCU
920
AGACCAAUUUAUGCCUACA
376
885
GAUGUGUCUGCGGCGUUUU
926
AAAACGCCGCAGACACAUC
413
895
CUGCUGCUAUGCCUCAUCU
936
AGAUGAGGCAUAGCAGCAG
1580
900
UGCACUUCGCUUCACCUCU
941
AGAGGUGAAGCGAAGUGCA
1818
888
AACUUUUUCACCUCUGCCU
929
AGGCAGAGGUGAAAAAGUU
33 . A method for preventing, ameliorating or treating a disease or condition associated with HBV infection in a subject in need, the method comprising administering to the subject an effective amount of a composition of claim 25 .
34 . The method of claim 33 , wherein the administration of the composition reduces HBV viral titer in the subject.
35 . The method of claim 33 , wherein the subject has been diagnosed with a disease associated with Hepatitis B virus infection.
36 . The method of claim 33 , wherein the subject has been diagnosed with liver disease.
37 . A method for inhibiting the replication, maturation, growth, or transmission of a Hepatitis B virus in a subject in need, the method comprising administering to the subject an effective amount of a composition of claim 25 .
38 . The method of claim 37 , wherein the administration of the composition reduces serum concentration of HBsAg in the subject.
39 . The method of claim 37 , wherein the administration of the composition reduces serum concentration of HBsAg in the subject by 2-log 10 -fold.
40 . The method of claim 37 , wherein the administration of the composition reduces serum concentration of HBsAg in the subject by 2-log 10 -fold for at least 7 days.
41 . The method of claim 37 , wherein the administration of the composition reduces HBeAg in the subject.
42 . The method of claim 37 , wherein the administration of the composition reduces HBV DNA in the subject.
43 . A method for inhibiting expression of a Hepatitis B virus polynucleotide in a subject in need, the method comprising administering to the subject a composition of claim 25 .Join the waitlist — get patent alerts
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