JPWO2021119226A5 - - Google Patents

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JPWO2021119226A5
JPWO2021119226A5 JP2022535508A JP2022535508A JPWO2021119226A5 JP WO2021119226 A5 JPWO2021119226 A5 JP WO2021119226A5 JP 2022535508 A JP2022535508 A JP 2022535508A JP 2022535508 A JP2022535508 A JP 2022535508A JP WO2021119226 A5 JPWO2021119226 A5 JP WO2021119226A5
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dsrna agent
nucleotides
nucleotide
modification
pharmaceutical composition
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JP2023506181A (en
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Priority claimed from PCT/US2020/064159 external-priority patent/WO2021119226A1/en
Publication of JP2023506181A publication Critical patent/JP2023506181A/en
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Ｃ９ｏｒｆ７２の発現を阻害するための二本鎖リボ核酸（ｄｓＲＮＡ）剤であって、
(ａ）ｄｓＲＮＡ剤は、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、センス鎖は、配列番号１３３のヌクレオチド２００－２７０と３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含み、アンチセンス鎖は、配列番号１３４の対応するヌクレオチド配列からの少なくとも１５個の連続するヌクレオチドを含み、ここでセンス鎖の全てのヌクレオチドおよびアンチセンス鎖の全てのヌクレオチドがヌクレオチド修飾を含む、およびここでｄｓＲＮＡ剤は少なくとも１つのホスホロチオエートヌクレオチド間連結を含む、または
（ｂ）ｄｓＲＮＡ剤は、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、センス鎖は、表１０Ａ、１０Ｂ、１２～１５、１９、２０、もしくは２１のいずれか１つに記載のアンチセンスヌクレオチド配列のいずれか１つと３個以下のヌクレオチドが異なる少なくとも１５個の連続するヌクレオチドを含む、または
（ｃ）ｄｓＲＮＡ剤は、二本鎖領域を形成するセンス鎖およびアンチセンス鎖を含み、アンチセンス鎖は、配列番号１２５のヌクレオチド配列と３個以下のヌクレオチドが異なる少なくとも１５個の連続するヌクレオチドを含む、ｄｓＲＮＡ剤。 A double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of C9orf72, the agent comprising:
(a) The dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, the sense strand comprising at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from nucleotides 200-270 of SEQ ID NO: 133. wherein the antisense strand comprises at least 15 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 134, wherein every nucleotide of the sense strand and every nucleotide of the antisense strand comprises a nucleotide modification. and wherein the dsRNA agent comprises at least one phosphorothioate internucleotide linkage, or
(b) the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, where the sense strand is as described in any one of Tables 10A, 10B, 12-15, 19, 20, or 21; comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the antisense nucleotide sequences, or
(c) the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, the antisense strand comprising at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 125; dsRNA agents, including . アンチセンス鎖が、以下：
５’－ＡＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣＵＣ－３’；
５’－ＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣＵ－３’；
５’－ＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣ－３’；
５’－ＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣ－３’；
５’－ＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣ－３’；
５’－ＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡ－３’；
５’－ＡＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣ－３’；
５’－ＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵ－３’；
５’－ＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧ－３’；
５’－ＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵ－３’；
５’－ＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵ－３’；
５’－ＡＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣ－３’；
５’－ＡＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵ－３’；
５’－ＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵ－３’；
５’－ＡＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵ－３’；
５’－ＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵ－３’；
５’－ＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣ－３’；
５’－ＡＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵ－３’；
５’－ＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧ－３’；
５’－ＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧ－３’；
５’－ＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡ－３’；
５’－ＡＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵ－３’；
５’－ＵＧＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡ－３’；および
５’－ＡＣＵＵＧＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵ－３’からなる群から選択されるアンチセンス鎖ヌクレオチド配列のいずれか１つと３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含む、請求項１に記載のｄｓＲＮＡ剤。 The antisense strand is:
5'-AAGGUCUUUUCUUGUUCACCUCC-3';
5'-UCAGGUCUUUUCUUGUUCACCCU-3';
5'-AUCAGGUCUUUUCUUGUUCACCC-3';
5'-UAUCAGGUCUUUUCUUGUUCACC-3';
5'-UUAUCAGGUCUUUUCUUGUUCAC-3';
5'-UUUAUCAGGUCUUUUCUUGUUCA-3';
5'-AUUUAUCAGGUCUUUUCUUGUUC-3';
5'-AUCUUUAUCAGGUCUUUUCUUGU-3';
5'-AAUCUUUAUCAGGUCUUUUCUUG-3';
5'-UAAUCUUUAUCAGGUCUUUUCUU-3';
5'-UUAAUCUUUAUCAGGUCUUUUCU-3';
5'-AUUAAUCUUUAUCAGGUCUUUUC-3';
5'-AGUUAAUCUUUAUCAGGUCUUUU-3';
5'-UGGUUAAUCUUUAUCAGGUCUUU-3';
5'-AUGGUUAAUCUUUAUCAGGUCUU-3';
5'-UCUGGUUAAUCUUUAUCAGGUCU-3';
5'-UUCUGGUUAAUCUUUAUCAGGUC-3';
5'-AUUCUGGUUAAUCUUUAUCAGGU-3';
5'-UCUUCUGGUUAAUCUUUAUCAGG-3';
5'-UUCUUCUGGUUAAUCUUUAUCAG-3';
5'-UUUCUUCUGGUUAAUCUUUAUCA-3';
5'-AUUUUCUUCUGGUUAAUCUUUAU-3';
5'-UGUUUUCUUCUGGUUAAUCUUUA-3'; and
2. The dsRNA agent of claim 1 , comprising at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the antisense strand nucleotide sequences selected from the group consisting of 5'-ACUUGUUUUCUUCUGGUUAAUCU-3' . センス鎖が、以下：
５’－ＧＧＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＵ－３’；
５’－ＧＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡ－３’；
５’－ＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵ－３’；
５’－ＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡ－３’；
５’－ＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡ－３’；
５’－ＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡ－３’；
５’－ＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＵ－３’；
５’－ＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵ－３’；
５’－ＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵ－３’；
５’－ＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡ－３’；
５’－ＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡ－３’；
５’－ＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＵ－３’；
５’－ＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＵ－３’；
５’－ＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡ－３’；
５’－ＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＵ－３’；
５’－ＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡ－３’；
５’－ＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡ－３’；
５’－ＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＵ－３’；
５’－ＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡ－３’；
５’－ＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡ－３’；
５’－ＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡ－３’；
５’－ＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＵ－３’；
５’－ＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＣＡ－３’；および
５’－ＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＣＡＡＧＵ－３’からなる群から選択されるセンス鎖ヌクレオチド配列のいずれか１つと３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含む、請求項１または２のいずれか一項に記載のｄｓＲＮＡ剤。 The sense strand is:
5'-GGGUGAACAAGAAAAGACCUU-3';
5'-GGUGAACAAGAAAAGACCUGA-3';
5'-GUGAACAAGAAAAGACCUGAU-3';
5'-UGAACAAGAAAAGACCUGAUA-3';
5'-GAACAAGAAAAGACCUGAUAA-3';
5'-AACAAGAAAAGACCUGAUAAA-3';
5'-ACAAGAAAAGACCUGAUAAAAU-3';
5'-AAGAAAAGACCUGAUAAAGAU-3';
5'-AGAAAAGACCUGAUAAAGAUU-3';
5'-GAAAAGACCUGAUAAAGAUUA-3';
5'-AAAAGACCUGAUAAAGAUUAA-3';
5'-AAAGACCUGAUAAAGAUUAAU-3';
5'-AAGACCUGAUAAAGAUUAACU-3';
5'-AGACCUGAUAAAGAUUAACCA-3';
5'-GACCUGAUAAAGAUUAACCAU-3';
5'-ACCUGAUAAAGAUUAACCAGA-3';
5'-CCUGAUAAAGAUUAACCAGAA-3';
5'-CUGAUAAAGAUUAACCAGAAU-3';
5'-UGAUAAAGAUUAACCAGAAGA-3';
5'-GAUAAAGAUUAACCAGAAGAA-3';
5'-AUAAAGAUUAACCAGAAAGAAA-3';
5'-AAAGAUUAACCAGAAGAAAAU-3';
5'-AAGAUUAACCAGAAGAAAACA-3'; and
3. Any one of claims 1 or 2 comprising at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the sense strand nucleotide sequences selected from the group consisting of 5'-AUUAACCAGAAGAAAAAAGU-3'. dsRNA agent described in. センス鎖およびアンチセンス鎖のヌクレオチド配列が、以下：
５’－ＧＧＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＵ－３’および
５’－ＡＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣＵＣ－３’；
５’－ＧＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡ－３’および
５’－ＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣＵ－３’；
５’－ＧＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵ－３’および
５’－ＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣＣ－３’；
５’－ＵＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡ－３’および
５’－ＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣＣ－３’；
５’－ＧＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡ－３’および
５’－ＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡＣ－３’；
５’－ＡＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡ－３’および
５’－ＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡ－３’；
５’－ＡＣＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＵ－３’および
５’－ＡＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣ－３’；
５’－ＡＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵ－３’および
５’－ＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵ－３’；
５’－ＡＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵ－３’および
５’－ＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧ－３’；
５’－ＧＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡ－３’および
５’－ＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵ－３’；
５’－ＡＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡ－３’および
５’－ＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵ－３’；
５’－ＡＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＵ－３’および
５’－ＡＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣ－３’；
５’－ＡＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＵ－３’および
５’－ＡＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵ－３’；
５’－ＡＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡ－３’および
５’－ＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵ－３’；
５’－ＧＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＵ－３’および
５’－ＡＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵ－３’；
５’－ＡＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡ－３’および
５’－ＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵ－３’；
５’－ＣＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡ－３’および
５’－ＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣ－３’；
５’－ＣＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＵ－３’および
５’－ＡＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵ－３’；
５’－ＵＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡ－３’および
５’－ＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧ－３’；
５’－ＧＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡ－３’および
５’－ＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧ－３’；
５’－ＡＵＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡ－３’および
５’－ＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡ－３’；
５’－ＡＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＵ－３’および
５’－ＡＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵ－３’；
５’－ＡＡＧＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＣＡ－３’および
５’－ＵＧＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡ－３’；ならびに
５’－ＡＵＵＡＡＣＣＡＧＡＡＧＡＡＡＡＣＡＡＧＵ－３’および
５’－ＡＣＵＵＧＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵ－３’からなる群から選択されるセンス鎖およびアンチセンス鎖のヌクレオチド配列のいずれか１つと３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含む、請求項１～３のいずれか一項に記載のｄｓＲＮＡ剤。 The nucleotide sequences of the sense and antisense strands are as follows:
5'-GGGUGAACAAGAAAAGACCUU-3' and
5'-AAGGUCUUUUCUUGUUCACCUCC-3';
5'-GGUGAACAAGAAAAGACCUGA-3' and
5'-UCAGGUCUUUUCUUGUUCACCCU-3';
5'-GUGAACAAGAAAAGACCUGAU-3' and
5'-AUCAGGUCUUUUCUUGUUCACCC-3';
5'-UGAACAAGAAAAGACCUGAUA-3' and
5'-UAUCAGGUCUUUUCUUGUUCACC-3';
5'-GAACAAGAAAAGACCUGAUAA-3' and
5'-UUAUCAGGUCUUUUCUUGUUCAC-3';
5'-AACAAGAAAAGACCUGAUAAA-3' and
5'-UUUAUCAGGUCUUUUCUUGUUCA-3';
5'-ACAAGAAAAGACCUGAUAAAAU-3' and
5'-AUUUAUCAGGUCUUUUCUUGUUC-3';
5'-AAGAAAAGACCUGAUAAAGAU-3' and
5'-AUCUUUAUCAGGUCUUUUCUUGU-3';
5'-AGAAAAGACCUGAUAAAGAUU-3' and
5'-AAUCUUUAUCAGGUCUUUUCUUG-3';
5'-GAAAAGACCUGAUAAAGAUUA-3' and
5'-UAAUCUUUAUCAGGUCUUUUCUU-3';
5'-AAAAGACCUGAUAAAGAUUAA-3' and
5'-UUAAUCUUUAUCAGGUCUUUUCU-3';
5'-AAAGACCUGAUAAAGAUUAAU-3' and
5'-AUUAAUCUUUAUCAGGUCUUUUC-3';
5'-AAGACCUGAUAAAGAUUAACU-3' and
5'-AGUUAAUCUUUAUCAGGUCUUUU-3';
5'-AGACCUGAUAAAGAUUAACCA-3' and
5'-UGGUUAAUCUUUAUCAGGUCUUU-3';
5'-GACCUGAUAAAGAUUAACCAU-3' and
5'-AUGGUUAAUCUUUAUCAGGUCUU-3';
5'-ACCUGAUAAAGAUUAACCAGA-3' and
5'-UCUGGUUAAUCUUUAUCAGGUCU-3';
5'-CCUGAUAAAGAUUAACCAGAA-3' and
5'-UUCUGGUUAAUCUUUAUCAGGUC-3';
5'-CUGAUAAAGAUUAACCAGAAU-3' and
5'-AUUCUGGUUAAUCUUUAUCAGGU-3';
5'-UGAUAAAGAUUAACCAGAAGA-3' and
5'-UCUUCUGGUUAAUCUUUAUCAGG-3';
5'-GAUAAAGAUUAACCAGAAGAA-3' and
5'-UUCUUCUGGUUAAUCUUUAUCAG-3';
5'-AUAAAGAUUAACCAGAAAGAAA-3' and
5'-UUUCUUCUGGUUAAUCUUUAUCA-3';
5'-AAAGAUUAACCAGAAGAAAAU-3' and
5'-AUUUUCUUCUGGUUAAUCUUUAU-3';
5'-AAGAUUAACCAGAAGAAAACA-3' and
5'-UGUUUUCUUCUGGUUAAUCUUUA-3'; and
5'-AUUAACCAGAAGAAAAAAGU-3' and
5'-ACUUGUUUUUCUUCUGGUUAAUCU-3', comprising at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the nucleotide sequences of the sense strand and the antisense strand selected from the group consisting of 5'-ACUUGUUUUUCUUCUGGUUAAUCU-3' 3. The dsRNA agent according to any one of 3. センス鎖が、配列番号１３３のヌクレオチド２２５－２５２と３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含み、およびアンチセンス鎖が、配列番号１３４の対応するヌクレオチド配列からの少なくとも１５個の連続するヌクレオチドを含む、請求項１に記載のｄｓＲＮＡ剤。 The sense strand comprises at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from nucleotides 225-252 of SEQ ID NO: 133, and the antisense strand comprises at least 15 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 134. 2. The dsRNA agent of claim 1, comprising contiguous nucleotides. アンチセンス鎖が、以下： The antisense strand is:
５’－ＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣＡ－３’；5'-UUUAUCAGGUCUUUUCUUGUUCA-3';
５’－ＡＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵＵＣ－３’；5'-AUUUAUCAGGUCUUUUCUUGUUC-3';
５’－ＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧＵ－３’；5'-AUCUUUAUCAGGUCUUUUCUUGU-3';
５’－ＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵＧ－３’；5'-AAUCUUUAUCAGGUCUUUUCUUG-3';
５’－ＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵＵ－３’；5'-UAAUCUUUAUCAGGUCUUUUCUU-3';
５’－ＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣＵ－３’；5'-UUAAUCUUUAUCAGGUCUUUUCU-3';
５’－ＡＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵＣ－３’；および5'-AUUAAUCUUUAUCAGGUCUUUUC-3'; and
５’－ＡＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵＣＵＵＵＵ－３’からなる群から選択されるアンチセンス鎖ヌクレオチド配列のいずれか１つと３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含む、請求項５に記載のｄｓＲＮＡ剤。6. The dsRNA agent of claim 5, comprising at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the antisense strand nucleotide sequences selected from the group consisting of 5'-AGUUAAUCUUUAUCAGGUCUUUU-3'. センス鎖が、配列番号１３３のヌクレオチド２３８－２６２と３個以下のヌクレオチドが異なる少なくとも１７個の連続するヌクレオチドを含み、およびアンチセンス鎖が、配列番号１３４の対応するヌクレオチド配列からの少なくとも１５個の連続するヌクレオチドを含む、請求項１に記載のｄｓＲＮＡ剤。 The sense strand comprises at least 17 contiguous nucleotides that differ by no more than 3 nucleotides from nucleotides 238-262 of SEQ ID NO: 133, and the antisense strand comprises at least 15 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 134. 2. The dsRNA agent of claim 1, comprising contiguous nucleotides. アンチセンス鎖が、以下： The antisense strand is:
５’－ＡＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧＵ－３’；5'-AUUCUGGUUAAUCUUUAUCAGGU-3';
５’－ＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧＧ－３’；5'-UCUUCUGGUUAAUCUUUAUCAGG-3';
５’－ＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡＧ－３’；5'-UUCUUCUGGUUAAUCUUUAUCAG-3';
５’－ＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵＣＡ－３’；および5'-UUUCUUCUGGUUAAUCUUUAUCA-3'; and
５’－ＡＵＵＵＵＣＵＵＣＵＧＧＵＵＡＡＵＣＵＵＵＡＵ－３’からなる群から選択されるアンチセンス鎖ヌクレオチド配列のいずれか１つからの少なくとも１７個の連続するヌクレオチドを含む、請求項７に記載のｄｓＲＮＡ剤。8. The dsRNA agent of claim 7, comprising at least 17 contiguous nucleotides from any one of the antisense strand nucleotide sequences selected from the group consisting of 5'-AUUUUCUUCUGGUUAAUCUUUAU-3'. センス鎖、アンチセンス鎖、またはセンス鎖とアンチセンス鎖の両方が、１つまたは複数の親油性部分にコンジュゲートしている、請求項１～８のいずれか一項に記載のｄｓＲＮＡ剤。 A dsRNA agent according to any one of claims 1 to 8 , wherein the sense strand, the antisense strand, or both the sense and antisense strands are conjugated to one or more lipophilic moieties. 親油性部分が、ｄｓＲＮＡ剤の二本鎖領域中の１つまたは複数の内部位置にコンジュゲートしている、請求項９に記載のｄｓＲＮＡ剤。 10. The dsRNA agent of claim 9 , wherein the lipophilic moiety is conjugated to one or more internal positions in the double-stranded region of the dsRNA agent. 親油性部分が、リンカーまたは担体を介してコンジュゲートしている、請求項９または１０に記載のｄｓＲＮＡ剤。 11. The dsRNA agent according to claim 9 or 10 , wherein the lipophilic moiety is conjugated via a linker or carrier. ヌクレオチド修飾の少なくとも１つが、デオキシヌクレオチド修飾、３’末端デオキシチミン（ｄＴ）ヌクレオチド修飾、２’Ｏ－メチルヌクレオチド修飾、２’フルオロヌクレオチド修飾、２’デオキシヌクレオチド修飾、ロックドヌクレオチド修飾、非ロックドヌクレオチド修飾、立体配座的に制限されたヌクレオチド修飾、拘束エチルヌクレオチド修飾、脱塩基ヌクレオチド修飾、２’－アミノヌクレオチド修飾、２’－Ｏ－アリルヌクレオチド修飾、２’－Ｃ－アルキルヌクレオチド修飾、２’－ヒドロキシルヌクレオチド修飾、２’－メトキシエチルヌクレオチド修飾、２’－Ｏ－アルキルヌクレオチド修飾、モルホリノヌクレオチド修飾、ホスホルアミデートヌクレオチド修飾、非天然塩基を含むヌクレオチド修飾、テトラヒドロピランヌクレオチド修飾、１，５－アンヒドロヘキシトールヌクレオチド修飾、シクロヘキセニルヌクレオチド修飾、５’ホスホロチオエート基修飾を含むヌクレオチド、５’メチルホスホネート基修飾を含むヌクレオチド、５’リン酸または５’リン酸ミミック修飾を含むヌクレオチド、ビニルホスホネート修飾を含むヌクレオチド、アデノシン－グリコール核酸（ＧＮＡ）修飾を含むヌクレオチド、チミジン－グリコール核酸（ＧＮＡ）Ｓ－異性体修飾を含むヌクレオチド、２－ヒドロキシメチル－テトラヒドロフラン－５－ホスフェート修飾を含むヌクレオチド、２’－デオキシチミジン－３’ホスフェート修飾を含むヌクレオチド、２’－デオキシグアノシン－３’－ホスフェート修飾を含むヌクレオチド、ならびにコレステリル誘導体およびドデカン酸ビスデシルアミド基修飾に連結された末端ヌクレオチド、ならびにそれらの組合せ、からなる群から選択される、請求項１～１１のいずれか一項に記載のｄｓＲＮＡ剤。 At least one of the nucleotide modifications is deoxynucleotide modification , 3' terminal deoxythymine (dT) nucleotide modification , 2'O-methyl nucleotide modification , 2' fluoronucleotide modification , 2' deoxynucleotide modification , locked nucleotide modification , Unlocked nucleotide modifications , conformationally restricted nucleotide modifications , constrained ethyl nucleotide modifications , abasic nucleotide modifications , 2'- amino nucleotide modifications , 2'-O- allyl nucleotide modifications , 2'-C- Alkyl nucleotide modification , 2'- hydroxyl nucleotide modification , 2'- methoxyethyl nucleotide modification , 2'-O- alkyl nucleotide modification, morpholino nucleotide modification , phosphoramidate nucleotide modification , nucleotide modification containing non-natural bases, Tetrahydropyran nucleotide modification , 1,5-anhydrohexitol nucleotide modification , cyclohexenyl nucleotide modification , nucleotide containing 5' phosphorothioate group modification , nucleotide containing 5' methylphosphonate group modification , 5' phosphate or 5' Nucleotides containing phosphate mimic modification , nucleotides containing vinylphosphonate modification , nucleotides containing adenosine-glycol nucleic acid (GNA) modification , nucleotides containing thymidine-glycol nucleic acid (GNA) S-isomer modification , 2-hydroxymethyl-tetrahydrofuran- Linked to nucleotides containing 5-phosphate modifications , nucleotides containing 2'-deoxythymidine-3' phosphate modifications , nucleotides containing 2'-deoxyguanosine-3'-phosphate modifications , and cholesteryl derivatives and dodecanoic acid bisdecylamide group modifications 12. The dsRNA agent according to any one of claims 1 to 11 , wherein the dsRNA agent is selected from the group consisting of : ６～８個のホスホロチオエートインターヌクレオチド連結を含む、請求項１～１２のいずれか一項に記載のｄｓＲＮＡ剤。 dsRNA agent according to any one of claims 1 to 12 , comprising 6 to 8 phosphorothioate internucleotide linkages. 少なくとも１つの鎖が、少なくとも１ヌクレオチドの３’オーバーハングを含む、または少なくとも１つの鎖が、少なくとも２ヌクレオチドの３’オーバーハングを含む、請求項１～１３のいずれか一項に記載のｄｓＲＮＡ剤。 14. The dsRNA agent of any one of claims 1-13 , wherein at least one strand comprises a 3' overhang of at least 1 nucleotide, or wherein at least one strand comprises a 3' overhang of at least 2 nucleotides. . 二本鎖領域が、１７～３０ヌクレオチド対の長さである、請求項１～１４のいずれか一項に記載のｄｓＲＮＡ剤。 15. The dsRNA agent according to any one of claims 1 to 14 , wherein the double-stranded region is 17 to 30 nucleotide pairs in length. 各鎖が、独立して１７～３０ヌクレオチドの長さである、請求項１～１５のいずれか一項に記載のｄｓＲＮＡ剤。 16. A dsRNA agent according to any one of claims 1 to 15 , wherein each strand is independently 17 to 30 nucleotides in length. 各鎖が、独立して１７～２５ヌクレオチドの長さである、請求項１～１５のいずれか一項に記載のｄｓＲＮＡ剤。 16. A dsRNA agent according to any one of claims 1 to 15 , wherein each strand is independently 17 to 25 nucleotides in length. 各鎖が、独立して２１～２３ヌクレオチドの長さである、請求項１～１５のいずれか一項に記載のｄｓＲＮＡ剤。 16. A dsRNA agent according to any one of claims 1 to 15 , wherein each strand is independently 21 to 23 nucleotides in length. １つまたは複数の親油性部分が、各鎖の５’末端から数えて、センス鎖における４～８位および１３～１８位、ならびにアンチセンス鎖における６～１０位および１５～１８位からなる群から選択される内部位置の１つまたは複数にコンジュゲートしている、請求項９～１８のいずれか一項に記載のｄｓＲＮＡ剤。 one or more lipophilic moieties consisting of positions 4-8 and 13-18 on the sense strand and positions 6-10 and 15-18 on the antisense strand, counting from the 5' end of each strand; 19. A dsRNA agent according to any one of claims 9 to 18 , conjugated to one or more internal locations selected from: １つまたは複数の親油性部分が、各鎖の５’末端から数えて、センス鎖における５、６、７、１５、および１７位、ならびにアンチセンス鎖における１５および１７位からなる群から選択される内部位置の１つまたは複数にコンジュゲートしている、請求項１９に記載のｄｓＲＮＡ剤。 The one or more lipophilic moieties are selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand and positions 15 and 17 on the antisense strand, counting from the 5' end of each strand. 20. The dsRNA agent of claim 19 , wherein the dsRNA agent is conjugated to one or more of the internal locations. 親油性部分が、飽和または不飽和Ｃ４～Ｃ３０炭化水素鎖と、ヒドロキシル、アミン、カルボン酸、スルホネート、ホスフェート、チオール、アジド、およびアルキンからなる群から選択される適宜の官能基とを含有する、請求項９～２０のいずれか一項に記載のｄｓＲＮＡ剤。 the lipophilic moiety contains a saturated or unsaturated C4-C30 hydrocarbon chain and a suitable functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne; dsRNA agent according to any one of claims 9 to 20 . 親油性部分が、飽和または不飽和Ｃ６～Ｃ１８炭化水素鎖を含有する、請求項２１に記載のｄｓＲＮＡ剤。 22. The dsRNA agent of claim 21 , wherein the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain. 親油性部分が、飽和または不飽和Ｃ１６炭化水素鎖を含有する、請求項２１に記載のｄｓＲＮＡ剤。 22. The dsRNA agent of claim 21 , wherein the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain. 飽和または不飽和Ｃ１６炭化水素鎖が、鎖の５’末端から数えて、６位にコンジュゲートされる、請求項２３に記載のｄｓＲＮＡ剤。 24. The dsRNA agent of claim 23 , wherein a saturated or unsaturated C16 hydrocarbon chain is conjugated at position 6 , counting from the 5' end of the chain. 親油性部分が、内部位置または二本鎖領域における１つまたは複数のヌクレオチドに置き換わる担体を介してコンジュゲートされる、請求項９～２４のいずれか一項に記載のｄｓＲＮＡ剤。 25. A dsRNA agent according to any one of claims 9 to 24 , wherein the lipophilic moiety is conjugated via a carrier replacing one or more nucleotides in an internal position or in a double-stranded region. 親油性部分が、核酸塩基、糖部分、またはヌクレオシド間連結にコンジュゲートされる、請求項９～２５のいずれか一項に記載のｄｓＲＮＡ剤。 26. A ds RNA agent according to any one of claims 9 to 25 , wherein the lipophilic moiety is conjugated to a nucleobase, a sugar moiety, or an internucleoside linkage. アンチセンス鎖の５’端におけるリン酸またはリン酸ミミックをさらに含む、請求項１～２６のいずれか一項に記載のｄｓＲＮＡ剤。 27. The dsRNA agent according to any one of claims 1 to 26 , further comprising a phosphate or phosphate mimic at the 5' end of the antisense strand. 請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤を含有する細胞。 A cell containing a dsRNA agent according to any one of claims 1 to 27 . 請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤を含む、Ｃ９ｏｒｆ７２の発現を阻害するための医薬組成物。 A pharmaceutical composition for inhibiting the expression of C9orf72, comprising a dsRNA agent according to any one of claims 1 to 27 . 細胞におけるＣ９ｏｒｆ７２の発現を阻害するインビトロ方法であって、細胞を、請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤または請求項２９に記載の医薬組成物と接触させること、それによって細胞におけるＣ９ｏｒｆ７２の発現を阻害することを含む、方法。 30. An in vitro method of inhibiting the expression of C9orf72 in a cell, comprising: contacting a cell with a dsRNA agent according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 29 , thereby inhibiting the expression of C9orf72 in a cell. A method comprising inhibiting expression of C9orf72 in. Ｃ９ｏｒｆ７２発現の低減によって利益を得ると予想される障害を有する対象を処置する方法における使用のための医薬組成物であって、治療有効量の請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤または請求項２９に記載の医薬組成物を含む、医薬組成物。 28. A pharmaceutical composition for use in a method of treating a subject having a disorder expected to benefit from reduction of C9orf72 expression, comprising a therapeutically effective amount of dsRNA according to any one of claims 1 to 27 . A pharmaceutical composition comprising an agent or a pharmaceutical composition according to claim 29 . Ｃ９ｏｒｆ７２発現の低減によって利益を得ると予想される障害を有する対象における少なくとも１つの症状を予防する方法における使用のための医薬組成物であって、予防有効量の請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤または請求項２９に記載の医薬組成物を含む、医薬組成物。 28. A pharmaceutical composition for use in a method of preventing at least one condition in a subject having a disorder expected to benefit from reduction of C9orf72 expression, comprising a prophylactically effective amount of any one of claims 1 to 27 . 30. A pharmaceutical composition comprising a dsRNA agent according to claim 29 or a pharmaceutical composition according to claim 29 . 障害が、Ｃ９ｏｒｆ７２関連障害である、請求項３１または３２に記載の医薬組成物。 33. The pharmaceutical composition according to claim 31 or 32 , wherein the disorder is a C9orf72-related disorder. Ｃ９ｏｒｆ７２関連障害が、Ｃ９ｏｒｆ７２筋萎縮性側索硬化症／前頭側頭認知症およびＣ９ｏｒｆ７２伸張に起因するハンチントン様症候群からなる群から選択される、請求項３３に記載の医薬組成物。 34. The pharmaceutical composition of claim 33 , wherein the C9orf72 related disorder is selected from the group consisting of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia and Huntington-like syndrome due to C9orf72 expansion. 対象が、ヒトである、請求項３４に記載の医薬組成物。 35. The pharmaceutical composition according to claim 34 , wherein the subject is a human. ｄｓＲＮＡ剤または医薬組成物が、約０．０１ｍｇ／ｋｇから約５０ｍｇ／ｋｇの用量での投与のためのものである、請求項３１～３５のいずれか一項に記載の医薬組成物。 36. A pharmaceutical composition according to any one of claims 31 to 35 , wherein the dsRNA agent or pharmaceutical composition is for administration at a dose of about 0.01 mg/kg to about 50 mg/kg. ｄｓＲＮＡ剤または医薬組成物が、皮下投与または髄腔内投与のためのものである、請求項３１～３６のいずれか一項に記載の医薬組成物。 37. A pharmaceutical composition according to any one of claims 31 to 36 , wherein the dsRNA agent or pharmaceutical composition is for subcutaneous or intrathecal administration . 方法が、追加の治療剤を対象に投与することをさらに含む、請求項３１～３７のいずれか一項に記載の医薬組成物。 38. The pharmaceutical composition of any one of claims 31-37 , wherein the method further comprises administering to the subject an additional therapeutic agent. 請求項１～２７のいずれか一項に記載のｄｓＲＮＡ剤または請求項２９に記載の医薬組成物を含むキット、バイアルまたはシリンジ。 A kit , vial or syringe comprising a dsRNA agent according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 29 .
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US20200385737A1 (en) * 2019-03-29 2020-12-10 University Of Massachusetts OLIGONUCLEOTIDE-BASED MODULATION OF C9orf72
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JP2024521907A (en) 2021-06-04 2024-06-04 アルナイラム ファーマシューティカルズ， インコーポレイテッド Human chromosome 9 open reading frame 72 (C9ORF72) iRNA agent compositions and methods of use thereof
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WO2024107765A2 (en) 2022-11-14 2024-05-23 Regeneron Pharmaceuticals, Inc. Compositions and methods for fibroblast growth factor receptor 3-mediated delivery to astrocytes

Family Cites Families (251)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US4469863A (en) 1980-11-12 1984-09-04 Ts O Paul O P Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof
US5023243A (en) 1981-10-23 1991-06-11 Molecular Biosystems, Inc. Oligonucleotide therapeutic agent and method of making same
US4476301A (en) 1982-04-29 1984-10-09 Centre National De La Recherche Scientifique Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon
JPS5927900A (en) 1982-08-09 1984-02-14 Wakunaga Seiyaku Kk Oligonucleotide derivative and its preparation
FR2540122B1 (en) 1983-01-27 1985-11-29 Centre Nat Rech Scient NOVEL COMPOUNDS COMPRISING A SEQUENCE OF OLIGONUCLEOTIDE LINKED TO AN INTERCALATION AGENT, THEIR SYNTHESIS PROCESS AND THEIR APPLICATION
US4605735A (en) 1983-02-14 1986-08-12 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4948882A (en) 1983-02-22 1990-08-14 Syngene, Inc. Single-stranded labelled oligonucleotides, reactive monomers and methods of synthesis
US4824941A (en) 1983-03-10 1989-04-25 Julian Gordon Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems
US4587044A (en) 1983-09-01 1986-05-06 The Johns Hopkins University Linkage of proteins to nucleic acids
US5118800A (en) 1983-12-20 1992-06-02 California Institute Of Technology Oligonucleotides possessing a primary amino group in the terminal nucleotide
US5118802A (en) 1983-12-20 1992-06-02 California Institute Of Technology DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside
US5550111A (en) 1984-07-11 1996-08-27 Temple University-Of The Commonwealth System Of Higher Education Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
FR2567892B1 (en) 1984-07-19 1989-02-17 Centre Nat Rech Scient NOVEL OLIGONUCLEOTIDES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS AS MEDIATORS IN DEVELOPING THE EFFECTS OF INTERFERONS
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
US5430136A (en) 1984-10-16 1995-07-04 Chiron Corporation Oligonucleotides having selectably cleavable and/or abasic sites
US5258506A (en) 1984-10-16 1993-11-02 Chiron Corporation Photolabile reagents for incorporation into oligonucleotide chains
US4828979A (en) 1984-11-08 1989-05-09 Life Technologies, Inc. Nucleotide analogs for nucleic acid labeling and detection
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
FR2575751B1 (en) 1985-01-08 1987-04-03 Pasteur Institut NOVEL ADENOSINE DERIVATIVE NUCLEOSIDES, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5405938A (en) 1989-12-20 1995-04-11 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4762779A (en) 1985-06-13 1988-08-09 Amgen Inc. Compositions and methods for functionalizing nucleic acids
US5317098A (en) 1986-03-17 1994-05-31 Hiroaki Shizuya Non-radioisotope tagging of fragments
JPS638396A (en) 1986-06-30 1988-01-14 Wakunaga Pharmaceut Co Ltd Poly-labeled oligonucleotide derivative
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4920016A (en) 1986-12-24 1990-04-24 Linear Technology, Inc. Liposomes with enhanced circulation time
US5264423A (en) 1987-03-25 1993-11-23 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5276019A (en) 1987-03-25 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
ATE113059T1 (en) 1987-06-24 1994-11-15 Florey Howard Inst NUCLEOSIDE DERIVATIVES.
US5585481A (en) 1987-09-21 1996-12-17 Gen-Probe Incorporated Linking reagents for nucleotide probes
US5188897A (en) 1987-10-22 1993-02-23 Temple University Of The Commonwealth System Of Higher Education Encapsulated 2',5'-phosphorothioate oligoadenylates
US4924624A (en) 1987-10-22 1990-05-15 Temple University-Of The Commonwealth System Of Higher Education 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof
US5525465A (en) 1987-10-28 1996-06-11 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates and methods of production and applications of the same
DE3738460A1 (en) 1987-11-12 1989-05-24 Max Planck Gesellschaft MODIFIED OLIGONUCLEOTIDS
US5082830A (en) 1988-02-26 1992-01-21 Enzo Biochem, Inc. End labeled nucleotide probe
EP0406309A4 (en) 1988-03-25 1992-08-19 The University Of Virginia Alumni Patents Foundation Oligonucleotide n-alkylphosphoramidates
US5278302A (en) 1988-05-26 1994-01-11 University Patents, Inc. Polynucleotide phosphorodithioates
US5109124A (en) 1988-06-01 1992-04-28 Biogen, Inc. Nucleic acid probe linked to a label having a terminal cysteine
US5216141A (en) 1988-06-06 1993-06-01 Benner Steven A Oligonucleotide analogs containing sulfur linkages
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5262536A (en) 1988-09-15 1993-11-16 E. I. Du Pont De Nemours And Company Reagents for the preparation of 5'-tagged oligonucleotides
US5512439A (en) 1988-11-21 1996-04-30 Dynal As Oligonucleotide-linked magnetic particles and uses thereof
US5457183A (en) 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5599923A (en) 1989-03-06 1997-02-04 Board Of Regents, University Of Tx Texaphyrin metal complexes having improved functionalization
FR2645866B1 (en) 1989-04-17 1991-07-05 Centre Nat Rech Scient NEW LIPOPOLYAMINES, THEIR PREPARATION AND THEIR USE
US5391723A (en) 1989-05-31 1995-02-21 Neorx Corporation Oligonucleotide conjugates
US4958013A (en) 1989-06-06 1990-09-18 Northwestern University Cholesteryl modified oligonucleotides
US5143854A (en) 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
US5744101A (en) 1989-06-07 1998-04-28 Affymax Technologies N.V. Photolabile nucleoside protecting groups
US5451463A (en) 1989-08-28 1995-09-19 Clontech Laboratories, Inc. Non-nucleoside 1,3-diol reagents for labeling synthetic oligonucleotides
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5254469A (en) 1989-09-12 1993-10-19 Eastman Kodak Company Oligonucleotide-enzyme conjugate that can be used as a probe in hybridization assays and polymerase chain reaction procedures
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US5399676A (en) 1989-10-23 1995-03-21 Gilead Sciences Oligonucleotides with inverted polarity
CA2071510C (en) 1989-10-24 2004-07-06 Chris A. Buhr 2' modified oligonucleotides
US5264564A (en) 1989-10-24 1993-11-23 Gilead Sciences Oligonucleotide analogs with novel linkages
US5292873A (en) 1989-11-29 1994-03-08 The Research Foundation Of State University Of New York Nucleic acids labeled with naphthoquinone probe
US5177198A (en) 1989-11-30 1993-01-05 University Of N.C. At Chapel Hill Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates
CA2029273A1 (en) 1989-12-04 1991-06-05 Christine L. Brakel Modified nucleotide compounds
US5486603A (en) 1990-01-08 1996-01-23 Gilead Sciences, Inc. Oligonucleotide having enhanced binding affinity
US5587361A (en) 1991-10-15 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides having phosphorothioate linkages of high chiral purity
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US6783931B1 (en) 1990-01-11 2004-08-31 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US7037646B1 (en) 1990-01-11 2006-05-02 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5646265A (en) 1990-01-11 1997-07-08 Isis Pharmceuticals, Inc. Process for the preparation of 2'-O-alkyl purine phosphoramidites
US5670633A (en) 1990-01-11 1997-09-23 Isis Pharmaceuticals, Inc. Sugar modified oligonucleotides that detect and modulate gene expression
US5578718A (en) 1990-01-11 1996-11-26 Isis Pharmaceuticals, Inc. Thiol-derivatized nucleosides
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
US5852188A (en) 1990-01-11 1998-12-22 Isis Pharmaceuticals, Inc. Oligonucleotides having chiral phosphorus linkages
WO1991013080A1 (en) 1990-02-20 1991-09-05 Gilead Sciences, Inc. Pseudonucleosides and pseudonucleotides and their polymers
US5214136A (en) 1990-02-20 1993-05-25 Gilead Sciences, Inc. Anthraquinone-derivatives oligonucleotides
US5321131A (en) 1990-03-08 1994-06-14 Hybridon, Inc. Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling
US5470967A (en) 1990-04-10 1995-11-28 The Dupont Merck Pharmaceutical Company Oligonucleotide analogs with sulfamate linkages
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
GB9009980D0 (en) 1990-05-03 1990-06-27 Amersham Int Plc Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides
DK0455905T3 (en) 1990-05-11 1998-12-07 Microprobe Corp Dipsticks for nucleic acid hybridization assays and method for covalent immobilization of oligonucleotides
US5618704A (en) 1990-07-27 1997-04-08 Isis Pharmacueticals, Inc. Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling
US5541307A (en) 1990-07-27 1996-07-30 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs and solid phase synthesis thereof
US5623070A (en) 1990-07-27 1997-04-22 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
JPH0874B2 (en) 1990-07-27 1996-01-10 アイシス・ファーマシューティカルス・インコーポレーテッド Nuclease-resistant, pyrimidine-modified oligonucleotides that detect and modulate gene expression
US5489677A (en) 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
US5610289A (en) 1990-07-27 1997-03-11 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogues
US5608046A (en) 1990-07-27 1997-03-04 Isis Pharmaceuticals, Inc. Conjugated 4'-desmethyl nucleoside analog compounds
US5138045A (en) 1990-07-27 1992-08-11 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5602240A (en) 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5218105A (en) 1990-07-27 1993-06-08 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5677437A (en) 1990-07-27 1997-10-14 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5688941A (en) 1990-07-27 1997-11-18 Isis Pharmaceuticals, Inc. Methods of making conjugated 4' desmethyl nucleoside analog compounds
US5245022A (en) 1990-08-03 1993-09-14 Sterling Drug, Inc. Exonuclease resistant terminally substituted oligonucleotides
WO1992002534A2 (en) 1990-08-03 1992-02-20 Sterling Drug, Inc. Compounds and methods for inhibiting gene expression
US5512667A (en) 1990-08-28 1996-04-30 Reed; Michael W. Trifunctional intermediates for preparing 3'-tailed oligonucleotides
US5214134A (en) 1990-09-12 1993-05-25 Sterling Winthrop Inc. Process of linking nucleosides with a siloxane bridge
US5561225A (en) 1990-09-19 1996-10-01 Southern Research Institute Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages
WO1992005186A1 (en) 1990-09-20 1992-04-02 Gilead Sciences Modified internucleoside linkages
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
ATE198598T1 (en) 1990-11-08 2001-01-15 Hybridon Inc CONNECTION OF MULTIPLE REPORTER GROUPS ON SYNTHETIC OLIGONUCLEOTIDES
GB9100304D0 (en) 1991-01-08 1991-02-20 Ici Plc Compound
US7015315B1 (en) 1991-12-24 2006-03-21 Isis Pharmaceuticals, Inc. Gapped oligonucleotides
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5371241A (en) 1991-07-19 1994-12-06 Pharmacia P-L Biochemicals Inc. Fluorescein labelled phosphoramidites
US5571799A (en) 1991-08-12 1996-11-05 Basco, Ltd. (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response
US5283185A (en) 1991-08-28 1994-02-01 University Of Tennessee Research Corporation Method for delivering nucleic acids into cells
EP0538194B1 (en) 1991-10-17 1997-06-04 Novartis AG Bicyclic nucleosides, oligonucleotides, their method of preparation and intermediates therein
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
EP1588761A3 (en) 1991-11-22 2005-11-23 Affymetrix, Inc. Method of forming arrays of polymers
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US6235887B1 (en) 1991-11-26 2001-05-22 Isis Pharmaceuticals, Inc. Enhanced triple-helix and double-helix formation directed by oligonucleotides containing modified pyrimidines
US5359044A (en) 1991-12-13 1994-10-25 Isis Pharmaceuticals Cyclobutyl oligonucleotide surrogates
EP0618925B2 (en) 1991-12-24 2012-04-18 Isis Pharmaceuticals, Inc. Antisense oligonucleotides
US6277603B1 (en) 1991-12-24 2001-08-21 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
US5565552A (en) 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5595726A (en) 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
FR2687679B1 (en) 1992-02-05 1994-10-28 Centre Nat Rech Scient OLIGOTHIONUCLEOTIDES.
DE4203923A1 (en) 1992-02-11 1993-08-12 Henkel Kgaa METHOD FOR PRODUCING POLYCARBOXYLATES ON A POLYSACCHARIDE BASE
US5633360A (en) 1992-04-14 1997-05-27 Gilead Sciences, Inc. Oligonucleotide analogs capable of passive cell membrane permeation
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
IL105914A0 (en) 1992-06-04 1993-10-20 Univ California Methods and compositions for in vivo gene therapy
WO1994000569A1 (en) 1992-06-18 1994-01-06 Genpharm International, Inc. Methods for producing transgenic non-human animals harboring a yeast artificial chromosome
EP0577558A2 (en) 1992-07-01 1994-01-05 Ciba-Geigy Ag Carbocyclic nucleosides having bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates
US5272250A (en) 1992-07-10 1993-12-21 Spielvogel Bernard F Boronated phosphoramidate compounds
WO1994002595A1 (en) 1992-07-17 1994-02-03 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of animal diseases
US6346614B1 (en) 1992-07-23 2002-02-12 Hybridon, Inc. Hybrid oligonucleotide phosphorothioates
US5574142A (en) 1992-12-15 1996-11-12 Microprobe Corporation Peptide linkers for improved oligonucleotide delivery
US5476925A (en) 1993-02-01 1995-12-19 Northwestern University Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups
ES2142934T3 (en) 1993-02-19 2000-05-01 Nippon Shinyaku Co Ltd DERIVATIVE OF GLYCEROL, DEVICE AND PHARMACEUTICAL COMPOSITION.
GB9304618D0 (en) 1993-03-06 1993-04-21 Ciba Geigy Ag Chemical compounds
DK0691968T3 (en) 1993-03-30 1998-02-23 Sanofi Sa Acyclic nucleoside analogs and oligonucleotide sequences containing these
EP0691977B1 (en) 1993-03-31 1997-11-26 Sanofi Oligonucleotides with amide linkages replacing phosphodiester linkages
DE4311944A1 (en) 1993-04-10 1994-10-13 Degussa Coated sodium percarbonate particles, process for their preparation and detergent, cleaning and bleaching compositions containing them
US6191105B1 (en) 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
US5955591A (en) 1993-05-12 1999-09-21 Imbach; Jean-Louis Phosphotriester oligonucleotides, amidites and method of preparation
US6015886A (en) 1993-05-24 2000-01-18 Chemgenes Corporation Oligonucleotide phosphate esters
US6294664B1 (en) 1993-07-29 2001-09-25 Isis Pharmaceuticals, Inc. Synthesis of oligonucleotides
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
JPH09507836A (en) 1993-11-16 1997-08-12 ジンタ・インコーポレイテッド Synthetic oligomers with chirally pure phosphonate-nucleosidyl bonds mixed with non-phosphonate-nucleoside bonds
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
US5519134A (en) 1994-01-11 1996-05-21 Isis Pharmaceuticals, Inc. Pyrrolidine-containing monomers and oligomers
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5599922A (en) 1994-03-18 1997-02-04 Lynx Therapeutics, Inc. Oligonucleotide N3'-P5' phosphoramidates: hybridization and nuclease resistance properties
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US5625050A (en) 1994-03-31 1997-04-29 Amgen Inc. Modified oligonucleotides and intermediates useful in nucleic acid therapeutics
US6054299A (en) 1994-04-29 2000-04-25 Conrad; Charles A. Stem-loop cloning vector and method
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US5543152A (en) 1994-06-20 1996-08-06 Inex Pharmaceuticals Corporation Sphingosomes for enhanced drug delivery
US5597696A (en) 1994-07-18 1997-01-28 Becton Dickinson And Company Covalent cyanine dye oligonucleotide conjugates
US5580731A (en) 1994-08-25 1996-12-03 Chiron Corporation N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith
US5597909A (en) 1994-08-25 1997-01-28 Chiron Corporation Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use
US5556752A (en) 1994-10-24 1996-09-17 Affymetrix, Inc. Surface-bound, unimolecular, double-stranded DNA
US6608035B1 (en) 1994-10-25 2003-08-19 Hybridon, Inc. Method of down-regulating gene expression
US6166197A (en) 1995-03-06 2000-12-26 Isis Pharmaceuticals, Inc. Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions
EP0813539B1 (en) 1995-03-06 2006-05-24 Isis Pharmaceuticals, Inc. Improved process for the synthesis of 2'-o-substituted pyrimidines and oligomeric compounds therefrom
WO1996037194A1 (en) 1995-05-26 1996-11-28 Somatix Therapy Corporation Delivery vehicles comprising stable lipid/nucleic acid complexes
US5981501A (en) 1995-06-07 1999-11-09 Inex Pharmaceuticals Corp. Methods for encapsulating plasmids in lipid bilayers
US5545531A (en) 1995-06-07 1996-08-13 Affymax Technologies N.V. Methods for making a device for concurrently processing multiple biological chip assays
EP0832271B8 (en) 1995-06-07 2005-03-02 INEX Pharmaceuticals Corp. Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
US7422902B1 (en) 1995-06-07 2008-09-09 The University Of British Columbia Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
US5858397A (en) 1995-10-11 1999-01-12 University Of British Columbia Liposomal formulations of mitoxantrone
US6160109A (en) 1995-10-20 2000-12-12 Isis Pharmaceuticals, Inc. Preparation of phosphorothioate and boranophosphate oligomers
US5854033A (en) 1995-11-21 1998-12-29 Yale University Rolling circle replication reporter systems
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
US5994316A (en) 1996-02-21 1999-11-30 The Immune Response Corporation Method of preparing polynucleotide-carrier complexes for delivery to cells
US6444423B1 (en) 1996-06-07 2002-09-03 Molecular Dynamics, Inc. Nucleosides comprising polydentate ligands
US6172209B1 (en) 1997-02-14 2001-01-09 Isis Pharmaceuticals Inc. Aminooxy-modified oligonucleotides and methods for making same
US6639062B2 (en) 1997-02-14 2003-10-28 Isis Pharmaceuticals, Inc. Aminooxy-modified nucleosidic compounds and oligomeric compounds prepared therefrom
US6576752B1 (en) 1997-02-14 2003-06-10 Isis Pharmaceuticals, Inc. Aminooxy functionalized oligomers
US6034135A (en) 1997-03-06 2000-03-07 Promega Biosciences, Inc. Dimeric cationic lipids
US6770748B2 (en) 1997-03-07 2004-08-03 Takeshi Imanishi Bicyclonucleoside and oligonucleotide analogue
JP3756313B2 (en) 1997-03-07 2006-03-15 武 今西 Novel bicyclonucleosides and oligonucleotide analogues
JP4656675B2 (en) 1997-05-14 2011-03-23 ユニバーシティー オブ ブリティッシュ コロンビア High rate encapsulation of charged therapeutic agents in lipid vesicles
US6887906B1 (en) 1997-07-01 2005-05-03 Isispharmaceuticals, Inc. Compositions and methods for the delivery of oligonucleotides via the alimentary canal
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
EP1557424A1 (en) 1997-09-12 2005-07-27 Exiqon A/S Bi-cyclic nucleoside, nucleotide and oligonucleoide analogues
US6617438B1 (en) 1997-11-05 2003-09-09 Sirna Therapeutics, Inc. Oligoribonucleotides with enzymatic activity
US6528640B1 (en) 1997-11-05 2003-03-04 Ribozyme Pharmaceuticals, Incorporated Synthetic ribonucleic acids with RNAse activity
US6320017B1 (en) 1997-12-23 2001-11-20 Inex Pharmaceuticals Corp. Polyamide oligomers
US7273933B1 (en) 1998-02-26 2007-09-25 Isis Pharmaceuticals, Inc. Methods for synthesis of oligonucleotides
US7045610B2 (en) 1998-04-03 2006-05-16 Epoch Biosciences, Inc. Modified oligonucleotides for mismatch discrimination
US6531590B1 (en) 1998-04-24 2003-03-11 Isis Pharmaceuticals, Inc. Processes for the synthesis of oligonucleotide compounds
US6867294B1 (en) 1998-07-14 2005-03-15 Isis Pharmaceuticals, Inc. Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages
JP2002520038A (en) 1998-07-20 2002-07-09 アイネックス ファーマシューティカルズ コーポレイション Liposome encapsulated nucleic acid complex
WO2000022113A1 (en) 1998-10-09 2000-04-20 Ingene, Inc. ENZYMATIC SYNTHESIS OF ssDNA
CA2345936A1 (en) 1998-10-09 2000-04-20 Ingene, Inc. Production of ssdna in a cell
US6465628B1 (en) 1999-02-04 2002-10-15 Isis Pharmaceuticals, Inc. Process for the synthesis of oligomeric compounds
WO2000050050A1 (en) 1999-02-23 2000-08-31 Isis Pharmaceuticals, Inc. Multiparticulate formulation
US7084125B2 (en) 1999-03-18 2006-08-01 Exiqon A/S Xylo-LNA analogues
NZ514348A (en) 1999-05-04 2004-05-28 Exiqon As L-ribo-LNA analogues
US6525191B1 (en) 1999-05-11 2003-02-25 Kanda S. Ramasamy Conformationally constrained L-nucleosides
US6593466B1 (en) 1999-07-07 2003-07-15 Isis Pharmaceuticals, Inc. Guanidinium functionalized nucleotides and precursors thereof
US6147200A (en) 1999-08-19 2000-11-14 Isis Pharmaceuticals, Inc. 2'-O-acetamido modified monomers and oligomers
AU2001227965A1 (en) 2000-01-21 2001-07-31 Geron Corporation 2'-arabino-fluorooligonucleotide n3'-p5'phosphoramidates: their synthesis and use
IT1318539B1 (en) 2000-05-26 2003-08-27 Italfarmaco Spa PROLONGED RELEASE PHARMACEUTICAL COMPOSITIONS FOR THE PARENTERAL ADMINISTRATION OF BIOLOGICALLY HYDROPHILE SUBSTANCES
DE60119562T2 (en) 2000-10-04 2007-05-10 Santaris Pharma A/S IMPROVED SYNTHESIS OF PURIN-BLOCKED NUCLEIC ACID ANALOGUE
US7063860B2 (en) 2001-08-13 2006-06-20 University Of Pittsburgh Application of lipid vehicles and use for drug delivery
WO2004007718A2 (en) 2002-07-10 2004-01-22 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Rna-interference by single-stranded rna molecules
US6878805B2 (en) 2002-08-16 2005-04-12 Isis Pharmaceuticals, Inc. Peptide-conjugated oligomeric compounds
CA2504694C (en) 2002-11-05 2013-10-01 Isis Pharmaceuticals, Inc. Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
AU2003290596B2 (en) 2002-11-05 2011-05-12 Isis Pharmaceuticals, Inc. Sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
EP1661905B9 (en) 2003-08-28 2012-12-19 IMANISHI, Takeshi Novel artificial nucleic acids of n-o bond crosslinkage type
EP1713915B1 (en) 2004-02-10 2009-12-16 Sirna Therapeutics, Inc. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING MULTIFUNCTIONAL SHORT INTERFERING NUCLEIC ACID (MULTIFUNCTIONAL siNA)
US7294754B2 (en) 2004-10-19 2007-11-13 Regeneron Pharmaceuticals, Inc. Method for generating an animal homozygous for a genetic modification
DK1866414T3 (en) 2005-03-31 2012-04-23 Calando Pharmaceuticals Inc Inhibitors of ribonucleotide reductase subunit 2 and uses thereof.
DK1984381T3 (en) 2006-01-27 2010-11-01 Isis Pharmaceuticals Inc 6-modified bicyclic nucleic acid analogues
US7569686B1 (en) 2006-01-27 2009-08-04 Isis Pharmaceuticals, Inc. Compounds and methods for synthesis of bicyclic nucleic acid analogs
EP1989307B1 (en) 2006-02-08 2012-08-08 Quark Pharmaceuticals, Inc. NOVEL TANDEM siRNAS
EP2021008B1 (en) 2006-04-07 2015-12-02 Idera Pharmaceuticals, Inc. Stabilized immune modulatory rna (simra) compounds for tlr7 and tlr8
CA2651453C (en) 2006-05-11 2014-10-14 Isis Pharmaceuticals, Inc. 5'-modified bicyclic nucleic acid analogs
CA2927045A1 (en) 2006-10-03 2008-04-10 Muthiah Manoharan Lipid containing formulations
US20100105134A1 (en) 2007-03-02 2010-04-29 Mdrna, Inc. Nucleic acid compounds for inhibiting gene expression and uses thereof
MX2009012568A (en) 2007-05-22 2009-12-08 Mdrna Inc Hydroxymethyl substituted rna oligonucleotides and rna complexes.
US8278425B2 (en) 2007-05-30 2012-10-02 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
DK2173760T4 (en) 2007-06-08 2016-02-08 Isis Pharmaceuticals Inc Carbocyclic bicyclic nukleinsyreanaloge
US8278283B2 (en) 2007-07-05 2012-10-02 Isis Pharmaceuticals, Inc. 6-disubstituted or unsaturated bicyclic nucleic acid analogs
CN102921003B (en) 2007-07-09 2014-11-26 艾德拉药物股份有限公司 Stabilized immune modulatory RNA (SIMRA) compounds
AU2008340355B2 (en) 2007-12-04 2015-01-22 Tekmira Pharmaceuticals Corporation Targeting lipids
DK2279254T3 (en) 2008-04-15 2017-09-18 Protiva Biotherapeutics Inc PRESENT UNKNOWN LIPID FORMS FOR NUCLEIC ACID ADMINISTRATION
EP2321414B1 (en) 2008-07-25 2018-01-10 Alnylam Pharmaceuticals, Inc. Enhancement of sirna silencing activity using universal bases or mismatches in the sense strand
US20100331389A1 (en) 2008-09-22 2010-12-30 Bob Dale Brown Compositions and methods for the specific inhibition of gene expression by dsRNA containing modified nucleotides
EP2355851B1 (en) 2008-11-10 2018-04-04 Arbutus Biopharma Corporation Novel lipids and compositions for the delivery of therapeutics
SG171879A1 (en) 2008-12-03 2011-07-28 Marina Biotech Inc Usirna complexes
US20100249214A1 (en) 2009-02-11 2010-09-30 Dicerna Pharmaceuticals Multiplex dicer substrate rna interference molecules having joining sequences
CN102325534B (en) 2008-12-18 2016-02-17 戴瑟纳制药公司 The DICER enzyme substrates extended and the method for specific inhibition of gene expression
EP2391343B1 (en) 2009-01-29 2017-03-01 Arbutus Biopharma Corporation Improved lipid formulation for the delivery of nucleic acids
US8883202B2 (en) 2009-05-05 2014-11-11 Tekmira Pharmaceuticals Corporation Lipid compositions
JP5875976B2 (en) 2009-06-01 2016-03-02 ヘイロー−バイオ アールエヌエーアイ セラピューティクス， インコーポレイテッド Polynucleotides, compositions and methods for their use for multivalent RNA interference
TR201811076T4 (en) 2009-06-10 2018-08-27 Arbutus Biopharma Corp Improved lipid formulation.
US9512164B2 (en) 2009-07-07 2016-12-06 Alnylam Pharmaceuticals, Inc. Oligonucleotide end caps
US8927513B2 (en) 2009-07-07 2015-01-06 Alnylam Pharmaceuticals, Inc. 5′ phosphate mimics
EP2960333B1 (en) 2009-08-27 2017-10-04 Idera Pharmaceuticals, Inc. Composition for inhibiting gene expression and uses thereof
US10913767B2 (en) 2010-04-22 2021-02-09 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising acyclic and abasic nucleosides and analogs
US20130190383A1 (en) 2010-04-26 2013-07-25 Marina Biotech, Inc. Nucleic acid compounds with conformationally restricted monomers and uses thereof
AU2012272908A1 (en) 2011-06-21 2013-12-19 Alnylam Pharmaceuticals, Inc. Assays and methods for determining activity of a therapeutic agent in a subject
SG11201401314PA (en) 2011-09-07 2014-09-26 Marina Biotech Inc Synthesis and uses of nucleic acid compounds with conformationally restricted monomers
IL293434B2 (en) 2011-11-18 2024-05-01 Alnylam Pharmaceuticals Inc Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases
DK2906696T4 (en) * 2012-10-15 2023-02-27 Ionis Pharmaceuticals Inc METHODS OF MODULATING C9ORF72 EXPRESSION
JP6995478B2 (en) 2013-05-01 2022-01-14 アイオーニス ファーマシューティカルズ， インコーポレーテッド Compositions and Methods for Regulating HBV and TTR Expression
WO2015116658A1 (en) 2014-01-31 2015-08-06 University Hospitals Systems and methods for intrathecal delivery of a pharmaceutical agent
JP7026678B2 (en) 2016-09-30 2022-02-28 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Non-human animal with hexanucleotide repeat elongation in C9ORF72 lous coition
US20210108199A1 (en) * 2017-09-06 2021-04-15 The Trustees Of Columbia University In The City Of New York Treatment for aggressive cancers by targeting C9ORF72
EP3681513A4 (en) 2017-09-14 2021-09-22 Arrowhead Pharmaceuticals, Inc. Rnai agents and compositions for inhibiting expression of angiopoietin-like 3 (angptl3), and methods of use
US20220125823A1 (en) * 2018-05-07 2022-04-28 Alnylam Pharmaceuticals, Inc. Extrahepatic delivery
KR20210148264A (en) 2019-04-04 2021-12-07 다이서나 파마수이티컬, 인크. Compositions and methods for inhibiting gene expression in the central nervous system

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