JPWO2021195307A5 - - Google Patents

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JPWO2021195307A5
JPWO2021195307A5 JP2022557819A JP2022557819A JPWO2021195307A5 JP WO2021195307 A5 JPWO2021195307 A5 JP WO2021195307A5 JP 2022557819 A JP2022557819 A JP 2022557819A JP 2022557819 A JP2022557819 A JP 2022557819A JP WO2021195307 A5 JPWO2021195307 A5 JP WO2021195307A5
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Priority claimed from PCT/US2021/024038 external-priority patent/WO2021195307A1/en
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細胞内でのコロナウイルスゲノムの発現を阻害するための二本鎖リボ核酸（ｄｓＲＮＡ）剤であって、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：
（ａ）アンチセンス鎖は、５’－ＧＵＵＵＧＡＡＡＡＧＣＡＡＣＡＵＵＧＵＵＡＧＵ－３’（配列番号６）のヌクレオチド配列と３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含む；
（ｂ）アンチセンス鎖は、５’－ＵＧＡＣＡＵＵＵＵＡＧＡＣＵＧＵＡＣＡＧＵＧＧ－３’（配列番号８）のヌクレオチド配列と３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含む；
（ｃ）センス鎖が、配列番号１のヌクレオチド配列の一部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号１のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含み、アンチセンス鎖が、配列番号２のヌクレオチド配列の対応する部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号２のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含む；
（ｄ）センス鎖が、配列番号２のヌクレオチド配列の一部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号２のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含み、アンチセンス鎖が、配列番号１のヌクレオチド配列の対応する部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号１のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含む；
（ｅ）アンチセンス鎖が、コロナウイルスゲノムをコードするｍＲＮＡ（配列番号１）の一部に対して相補的な領域を含み、各鎖が独立に、１４～３０ヌクレオチド長である；
（ｆ）アンチセンス鎖が、コロナウイルスゲノムをコードするｍＲＮＡの逆相補体（配列番号２）の一部に対して相補的な領域を含み、各鎖が独立に、１４～３０ヌクレオチド長である；または
（ｇ）アンチセンス鎖が、明細書中の表２－１～２－２２、３－１～３－２０、４－１～４－４、５－１～５－２のいずれか１つにおけるアンチセンスヌクレオチド配列のいずれか１つとは３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含み、各鎖が独立に、１４～３０ヌクレオチド長である、
ｄｓＲＮＡ剤。 A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a coronavirus genome in a cell, comprising a sense strand and an antisense strand forming a double-stranded region :
(a) the antisense strand comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from the nucleotide sequence of 5'-GUUUGAAAAGCAACAUUGUUAGU-3' (SEQ ID NO: 6);
(b) the antisense strand comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from the nucleotide sequence of 5'-UGACAUUUUAGACUGUACAGUGG-3' (SEQ ID NO: 8);
(c) a nucleotide sequence in which the sense strand comprises at least 15 contiguous nucleotides containing 0, 1, 2, or 3 mismatches of a portion of the nucleotide sequence of SEQ ID NO: 1, or of the nucleotide sequence of SEQ ID NO: 1; a nucleotide sequence having at least 90% nucleotide sequence identity to a portion, the antisense strand comprising 0, 1, 2, or 3 mismatches of the corresponding portion of the nucleotide sequence of SEQ ID NO:2. or having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of SEQ ID NO: 2 ;
(d) the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides containing 0, 1, 2, or 3 mismatches of a portion of the nucleotide sequence of SEQ ID NO: 2, or of the nucleotide sequence of SEQ ID NO: 2; 1, wherein the antisense strand contains 0, 1, 2, or 3 mismatches of the corresponding portion of the nucleotide sequence of SEQ ID NO: 1. or having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of SEQ ID NO: 1;
(e) the antisense strand includes a region complementary to a portion of the mRNA encoding the coronavirus genome (SEQ ID NO: 1), and each strand is independently 14 to 30 nucleotides long;
(f) The antisense strand contains a region complementary to a portion of the reverse complement (SEQ ID NO: 2) of the mRNA encoding the coronavirus genome, and each strand is independently 14 to 30 nucleotides long. ;or
(g) The antisense strand is in any one of Tables 2-1 to 2-22, 3-1 to 3-20, 4-1 to 4-4, and 5-1 to 5-2 in the specification. comprising at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the antisense nucleotide sequences, each strand independently being 14 to 30 nucleotides long;
dsRNA agent. センス鎖またはアンチセンス鎖が、１つまたは複数の親油性部分にコンジュゲートされる、請求項１に記載のｄｓＲＮＡ剤。 The dsRNA agent of claim 1 , wherein the sense strand or the antisense strand is conjugated to one or more lipophilic moieties. 少なくとも１つの修飾されたヌクレオチドを含む、請求項１または２に記載のｄｓＲＮＡ剤。 3. The dsRNA agent of claim 1 or 2 , comprising at least one modified nucleotide. 修飾ヌクレオチドの少なくとも１つが、デオキシ－ヌクレオチド、３’末端デオキシ－チミジン（ｄＴ）ヌクレオチド、２’－Ｏ－メチル修飾ヌクレオチド、２’－フルオロ修飾ヌクレオチド、２’－デオキシ－修飾ヌクレオチド、ロックドヌクレオチド、アンロックドヌクレオチド、立体配座制限ヌクレオチド、拘束エチルヌクレオチド、脱塩基ヌクレオチド、２’－アミノ－修飾ヌクレオチド、２’－Ｏ－アリル－修飾ヌクレオチド、２’－Ｃ－アルキル－修飾ヌクレオチド、２’－メトキシエチル修飾ヌクレオチド、２’－Ｏ－アルキル－修飾ヌクレオチド、モルホリノヌクレオチド、ホスホロアミデート、非天然塩基を含むヌクレオチド、テトラヒドロピラン修飾ヌクレオチド、１，５－アンヒドロヘキシトール修飾ヌクレオチド、シクロヘキセニル修飾ヌクレオチド、５’－ホスホロチオエート基を含むヌクレオチド、５’－メチルホスホネート基を含むヌクレオチド、５’ホスフェートまたは５’ホスフェート模倣物を含むヌクレオチド、ビニルホスホネートを含むヌクレオチド、アデノシン－グリコール核酸（ＧＮＡ）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’－ホスフェートを含むヌクレオチド、２’－Ｏヘキサデシルヌクレオチド、２’－ホスフェートを含むヌクレオチド、シチジン－２’－ホスフェートヌクレオチド、グアノシン－２’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－シチジン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－アデノシン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－グアノシン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－ウリジン－３’－ホスフェートヌクレオチド、５’－ビニルホスホネート（ＶＰ）、２’－デオキシアデノシン－３’－ホスフェートヌクレオチド、２’－デオキシシチジン－３’－ホスフェートヌクレオチド、２’－デオキシグアノシン－３’－ホスフェートヌクレオチド、２’－デオキシチミジン－３’－ホスフェートヌクレオチド、２’－デオキシウリジンヌクレオチド、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に連結し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３に記載のｄｓＲＮＡ剤。 At least one of the modified nucleotides is a deoxy-nucleotide, a 3'-terminal deoxy-thymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, a 2'-C-alkyl-modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-O-alkyl-modified nucleotide, a morpholino nucleotide, tides, phosphoramidates, nucleotides containing unnatural bases, tetrahydropyran modified nucleotides, 1,5-anhydrohexitol modified nucleotides, cyclohexenyl modified nucleotides, nucleotides containing 5'-phosphorothioate groups, nucleotides containing 5'-methylphosphonate groups, nucleotides containing 5' phosphates or 5' phosphate mimetics, nucleotides containing vinyl phosphonates, nucleotides containing adenosine-glycol nucleic acid (GNA), nucleotides containing thymidine-glycol nucleic acid (GNA) S isomers, 2-hydroxymethyl-tetrahydrofuran 2'-5-phosphate containing nucleotides, 2'-deoxythymidine-3' phosphate containing nucleotides, 2'-deoxyguanosine-3'-phosphate containing nucleotides, 2'-O hexadecyl nucleotides, 2'-phosphate containing nucleotides, cytidine-2'-phosphate nucleotides, guanosine-2'-phosphate nucleotides, 2'-O-hexadecyl-cytidine-3'-phosphate nucleotides, 2'-O-hexadecyl-adenosine-3'-phosphate nucleotides, 2'-O-hexadecyl-guanosine-3'-phosphate nucleotides, 2' 4. The dsRNA agent of claim 3, selected from the group consisting of -O-hexadecyl-uridine-3'-phosphate nucleotides, 5'-vinylphosphonate (VP), 2'-deoxyadenosine-3'-phosphate nucleotides, 2'-deoxycytidine-3'-phosphate nucleotides, 2'-deoxyguanosine-3'-phosphate nucleotides, 2'-deoxythymidine-3'- phosphate nucleotides, 2'-deoxyuridine nucleotides, and terminal nucleotides linked to cholesteryl derivatives and dodecanoic acid bisdecylamide groups, and combinations thereof. 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さらに含む、請求項１～４のいずれか一項に記載のｄｓＲＮＡ剤。 dsRNA agent according to any one of claims 1 to 4 , further comprising at least one phosphorothioate internucleotide linkage. 各鎖が、３０ヌクレオチド長以下である、請求項１～５のいずれか一項に記載のｄｓＲＮＡ剤。 The dsRNA agent of any one of claims 1 to 5 , wherein each strand is 30 nucleotides or less in length. 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、請求項１～６のいずれか一項に記載のｄｓＲＮＡ剤。 7. A dsRNA agent according to any one of claims 1 to 6 , wherein at least one strand comprises a 3' overhang of at least one nucleotide. 二本鎖領域が、１５～３０ヌクレオチド対の長さである、請求項１～７のいずれか一項に記載のｄｓＲＮＡ剤。 8. The dsRNA agent according to any one of claims 1 to 7 , wherein the double-stranded region is 15 to 30 nucleotide pairs in length. １つまたは複数の親油性部分が、少なくとも１つの鎖における１つまたは複数の内部位置にコンジュゲートされる、請求項２に記載のｄｓＲＮＡ剤。 3. The dsRNA agent of claim 2 , wherein one or more lipophilic moieties are conjugated to one or more internal positions in at least one strand. １つまたは複数の親油性部分が、各鎖の５’端から数えて、センス鎖における位置４～８および１３～１８ならびにアンチセンス鎖における位置６～１０および１５～１８からなる群から選択される記内部位置の１つまたは複数にコンジュゲートされる、請求項２～９のいずれか一項に記載のｄｓＲＮＡ剤。 10. The dsRNA agent of any one of claims 2 to 9, wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 in the sense strand and positions 6-10 and 15-18 in the antisense strand, counting from the 5 ' end of each strand. 親油性部分が、脂肪族化合物、脂環式化合物、または多脂環式化合物である、請求項２～１０のいずれか一項に記載のｄｓＲＮＡ剤。 The dsRNA agent according to any one of claims 2 to 10 , wherein the lipophilic moiety is an aliphatic compound, an alicyclic compound, or a polyalicyclic compound. 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１１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; 12. The dsRNA agent according to claim 11 . アンチセンス鎖の５’端におけるホスフェートまたはホスフェート模倣物をさらに含む、請求項１～１２のいずれか一項に記載のｄｓＲＮＡ剤。 The dsRNA agent of any one of claims 1 to 12 , further comprising a phosphate or a phosphate mimetic at the 5'-end of the antisense strand. センス鎖がヌクレオチド配列５’－ＵＡＡＣＡＡＵＧＵＵＧＣＵＵＵＵＣＡＡＡＣ－３’（配列番号５）を含み、アンチセンス鎖がヌクレオチド配列５’－ＧＵＵＵＧＡＡＡＡＧＣＡＡＣＡＵＵＧＵＵＡＧＵ－３’（配列番号６）を含む、請求項１～１３のいずれか一項に記載のｄｓＲＮＡ剤。 The dsRNA agent of any one of claims 1 to 13 , wherein the sense strand comprises the nucleotide sequence 5'-UAAACAAUGUUGCUUUUCAAAC-3' (SEQ ID NO:5) and the antisense strand comprises the nucleotide sequence 5'-GUUUGAAAAGCAACAUUGUUAGU-3' (SEQ ID NO:6). センス鎖がヌクレオチド配列５’－ＡＣＵＧＵＡＣＡＧＵＣＵＡＡＡＡＵＧＵＣＡ－３’（配列番号７）を含み、アンチセンス鎖がヌクレオチド配列５’－ＵＧＡＣＡＵＵＵＵＡＧＡＣＵＧＵＡＣＡＧＵＧＧ－３’（配列番号８）を含む、請求項１～１３のいずれか一項に記載のｄｓＲＮＡ剤。 Any one of claims 1 to 13 , wherein the sense strand comprises the nucleotide sequence 5'-ACUGUACAGUCUAAAAUGUCA-3' (SEQ ID NO: 7) and the antisense strand comprises the nucleotide sequence 5'-UGACAUUUUAGACUGUACAGUGG-3' (SEQ ID NO: 8). dsRNA agent described in section. センス鎖が、センス鎖ヌクレオチド配列５’－ｕｓａｓａｃａ（Ａｈｄ）ＵｆｇＵｆＵｆＧｆｃｕｕｕｕｃａａｓａｓａ－３’（配列番号９）を含み、アンチセンス鎖が、ヌクレオチド配列５’－ＶＰｕｓＵｆｓｕｕｇＡｆａａａｇｃａａＣｆａＵｆｕｇｕｕａｓｇｓｕ－３’（配列番号１０）を含み、
式中、ａ、ｇ、ｃおよびｕは、２’－Ｏ－メチル（２’－ＯＭｅ）Ａ、Ｇ、Ｃ、およびＵであり、Ａｆ、Ｇｆ、ＣｆおよびＵｆは、２’－フルオロＡ、Ｇ、ＣおよびＵであり、ｓは、ホスホロチオエート連結であり、（Ａｈｄ）は、２’－Ｏ－ヘキサデシル－アデノシン－３’－ホスフェートであり、ＶＰは、ビニル－ホスホネートである、請求項１４に記載のｄｓＲＮＡ剤。 The sense strand comprises the sense strand nucleotide sequence 5'-usasaca(Ahd)UfgUfUfGfcuuuucaasasa-3' (SEQ ID NO: 9), the antisense strand comprises the nucleotide sequence 5'-VPusUfsuugAfaaagcaaCfaUfuguuasgsu-3' (SEQ ID NO: 10),
where a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C, and U, and Af, Gf, Cf and Uf are 2'-fluoro A, 15. G, C and U, s is a phosphorothioate linkage, (Ahd) is 2'-O-hexadecyl-adenosine-3'-phosphate, and VP is vinyl-phosphonate. dsRNA agents as described. センス鎖が、ヌクレオチド配列５’－ａｓｃｓｕｇｕ（Ａｈｄ）ＣｆａＧｆＵｆＣｆｕａａａａｕｇｕｓｃｓａ－３’（配列番号１１）を含み、アンチセンス鎖が、ヌクレオチド配列５’－ＶＰｕｓＧｆｓａｃａＵｆｕｕｕａｇａｃＵｆｇＵｆａｃａｇｕｓｇｓｇ－３’（配列番号１２）を含み、
式中、ａ、ｇ、ｃおよびｕは、２’－Ｏ－メチル（２’－ＯＭｅ）Ａ、Ｇ、Ｃ、およびＵであり、Ａｆ、Ｇｆ、ＣｆおよびＵｆは、２’－フルオロＡ、Ｇ、ＣおよびＵであり、ｓは、ホスホロチオエート連結であり、（Ａｈｄ）は、２’－Ｏ－ヘキサデシル－アデノシン－３’－ホスフェートであり、ＶＰは、ビニル－ホスホネートである、請求項１５に記載のｄｓＲＮＡ剤。 The sense strand comprises the nucleotide sequence 5'-ascsugu(Ahd)CfaGfUfCfuaaaauguscsa-3' (SEQ ID NO: 11), the antisense strand comprises the nucleotide sequence 5'-VPusGfsacaUfuuuagacUfgUfacagusgsg-3' (SEQ ID NO: 12),
where a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C, and U, and Af, Gf, Cf and Uf are 2'-fluoro A, 16. G, C and U, s is a phosphorothioate linkage, (Ahd) is 2'-O-hexadecyl-adenosine-3'-phosphate, and VP is vinyl-phosphonate. dsRNA agents as described. 請求項１～１７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 17 . 請求項１～１７のいずれか一項に記載のｄｓＲＮＡ剤を含む、コロナウイルスゲノムの発現を阻害するための医薬組成物。 A pharmaceutical composition for inhibiting expression of a coronavirus genome, comprising a dsRNA agent according to any one of claims 1 to 17 . （ａ）細胞におけるコロナウイルスゲノムの発現を阻害するための第１の二本鎖ＲＮＡｉ剤、および細胞におけるコロナウイルスゲノムの発現を阻害するための第２の二本鎖ＲＮＡｉ剤、ここで、
第１の二本鎖ＲＮＡｉ剤は、第１の二本鎖領域を形成する第１のセンス鎖および第１のアンチセンス鎖を含み、第２の二本鎖ＲＮＡｉ剤は、第２の二本鎖領域を形成する第２のセンス鎖および第２のアンチセンス鎖を含み、
第１のアンチセンス鎖は、５’－ＧＵＵＵＧＡＡＡＡＧＣＡＡＣＡＵＵＧＵＵＡＧＵ－３’（配列番号６）のヌクレオチド配列と３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含み、
第２のアンチセンス鎖は、５’－ＵＧＡＣＡＵＵＵＵＡＧＡＣＵＧＵＡＣＡＧＵＧＧ－３’（配列番号８）のヌクレオチド配列と３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含む；
（ｂ）細胞内でのコロナウイルスゲノムの発現を阻害するための２つ以上の二本鎖ＲＮＡｉ剤、ここで、
各二本鎖ＲＮＡｉ剤が独立に、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、
センス鎖のそれぞれが独立に、配列番号１のヌクレオチド配列の一部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号１のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含み、アンチセンス鎖のそれぞれが独立に、配列番号２のヌクレオチド配列の対応する部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号２のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含む；
（ｃ）細胞内でのコロナウイルスゲノムの発現を阻害するための２つ以上の二本鎖リボ核酸（ｄｓＲＮＡ）剤、ここで、
各ｄｓＲＮＡ剤が独立に、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、
センス鎖のそれぞれが独立に、配列番号２のヌクレオチド配列の一部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号２のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含み、アンチセンス鎖のそれぞれが独立に、配列番号１のヌクレオチド配列の対応する部分の、０、１、２、もしくは３個のミスマッチを含む、少なくとも１５の連続するヌクレオチドを含むヌクレオチド配列、または配列番号１のヌクレオチド配列の一部分に対する少なくとも９０％のヌクレオチド配列同一性を有するヌクレオチド配列を含む；
（ｄ）細胞内でのコロナウイルスゲノムの発現を阻害するための２つ以上の二本鎖リボ核酸（ｄｓＲＮＡ）剤、ここで、
各ｄｓＲＮＡ剤が独立に、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、
アンチセンス鎖のそれぞれが独立に、コロナウイルスゲノムをコードするｍＲＮＡ（配列番号１）の一部に対して相補的な領域を含み、
センス鎖のそれぞれまたはアンチセンス鎖のそれぞれが独立に、１４～３０ヌクレオチド長である；
（ｅ）細胞内でのコロナウイルスゲノムの発現を阻害するための２つ以上の二本鎖リボ核酸（ｄｓＲＮＡ）剤、ここで、
各ｄｓＲＮＡ剤が独立に、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、
アンチセンス鎖のそれぞれが独立に、コロナウイルスゲノムをコードするｍＲＮＡの逆相補体（配列番号２）の一部に対して相補的な領域を含み、
センス鎖のそれぞれまたはアンチセンス鎖のそれぞれが独立に、１４～３０ヌクレオチド長である；または
（ｆ）細胞内でのコロナウイルスゲノムの発現を阻害するための２つ以上の二本鎖ＲＮＡｉ剤、ここで、
各二本鎖ＲＮＡｉ剤が独立に、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、
アンチセンス鎖のそれぞれが独立に、明細書中の表２－１～２－２２、３－１～３－２０、４－１～４－４、５－１～５－２のいずれか１つにおけるアンチセンスヌクレオチド配列のいずれか１つとは３ヌクレオチド以下異なる少なくとも１５の連続するヌクレオチドを含み、
センス鎖のそれぞれまたはアンチセンス鎖のそれぞれが独立に、１４～３０ヌクレオチド長である、
を含む組成物。 (a) a first double-stranded RNAi agent for inhibiting expression of a coronavirus genome in a cell; and a second double-stranded RNAi agent for inhibiting expression of a coronavirus genome in a cell, wherein:
The first double-stranded RNAi agent comprises a first sense strand and a first antisense strand forming a first double-stranded region, and the second double-stranded RNAi agent comprises a second double-stranded RNAi agent. a second sense strand and a second antisense strand forming a strand region;
the first antisense strand comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from the nucleotide sequence of 5'-GUUUGAAAAGCAACAUUGUUAGU-3' (SEQ ID NO: 6);
the second antisense strand comprises at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from the nucleotide sequence of 5'-UGACAUUUUAGACUGUACAGUGG-3' (SEQ ID NO: 8);
(b) two or more double-stranded RNAi agents for inhibiting expression of a coronavirus genome within a cell , wherein:
each double-stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region;
a nucleotide sequence comprising at least 15 contiguous nucleotides, each of the sense strands independently comprising 0, 1, 2, or 3 mismatches of a portion of the nucleotide sequence of SEQ ID NO: 1; or a nucleotide sequence of SEQ ID NO: 1; a nucleotide sequence having at least 90% nucleotide sequence identity to a portion, each of the antisense strands independently having 0, 1, 2, or 3 mismatches of the corresponding portion of the nucleotide sequence of SEQ ID NO: 2. or having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of SEQ ID NO: 2 ;
(c) two or more double-stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a coronavirus genome within a cell, wherein:
each dsRNA agent independently comprises a sense strand and an antisense strand forming a double-stranded region;
a nucleotide sequence comprising at least 15 contiguous nucleotides, each of the sense strands independently comprising 0, 1, 2, or 3 mismatches of a portion of the nucleotide sequence of SEQ ID NO: 2; or a nucleotide sequence of SEQ ID NO: 2; a nucleotide sequence having at least 90% nucleotide sequence identity to a portion, each of the antisense strands independently having 0, 1, 2, or 3 mismatches of the corresponding portion of the nucleotide sequence of SEQ ID NO: 1; or having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of SEQ ID NO: 1;
(d) two or more double-stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a coronavirus genome within a cell, wherein:
each dsRNA agent independently comprises a sense strand and an antisense strand forming a double-stranded region;
Each of the antisense strands independently includes a region complementary to a portion of mRNA (SEQ ID NO: 1) encoding the coronavirus genome,
Each of the sense strands or each of the antisense strands is independently 14-30 nucleotides in length;
(e) two or more double-stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a coronavirus genome within a cell , wherein:
each dsRNA agent independently comprises a sense strand and an antisense strand forming a double-stranded region;
Each of the antisense strands independently comprises a region complementary to a portion of the reverse complement (SEQ ID NO: 2) of the mRNA encoding the coronavirus genome;
each of the sense strands or each of the antisense strands is independently 14 to 30 nucleotides in length; or
(f) two or more double-stranded RNAi agents for inhibiting expression of a coronavirus genome within a cell, wherein:
each double-stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region;
Each of the antisense strands independently represents any one of Tables 2-1 to 2-22, 3-1 to 3-20, 4-1 to 4-4, and 5-1 to 5-2 in the specification. at least 15 contiguous nucleotides that differ by no more than 3 nucleotides from any one of the antisense nucleotide sequences in
each of the sense strands or each of the antisense strands is independently 14 to 30 nucleotides in length;
A composition comprising. 前記センス鎖の少なくとも１つまたは前記アンチセンス鎖の少なくとも１つが、１つまたは複数の親油性部分に独立にコンジュゲートされる、請求項２０に記載の組成物。 21. The composition of claim 20 , wherein at least one of the sense strands or at least one of the antisense strands is independently conjugated to one or more lipophilic moieties. ｄｓＲＮＡ剤のそれぞれが独立に少なくとも１つの修飾されたヌクレオチドを含む、請求項２０または２１に記載の組成物。 22. The composition of claim 20 or 21, wherein each of the dsRNA agents independently comprises at least one modified nucleotide. 修飾ヌクレオチドの少なくとも１つが、デオキシ－ヌクレオチド、３’末端デオキシ－チミジン（ｄＴ）ヌクレオチド、２’－Ｏ－メチル修飾ヌクレオチド、２’－フルオロ修飾ヌクレオチド、２’－デオキシ－修飾ヌクレオチド、ロックドヌクレオチド、アンロックドヌクレオチド、立体配座制限ヌクレオチド、拘束エチルヌクレオチド、脱塩基ヌクレオチド、２’－アミノ－修飾ヌクレオチド、２’－Ｏ－アリル－修飾ヌクレオチド、２’－Ｃ－アルキル－修飾ヌクレオチド、２’－メトキシエチル修飾ヌクレオチド、２’－Ｏ－アルキル－修飾ヌクレオチド、モルホリノヌクレオチド、ホスホロアミデート、非天然塩基を含むヌクレオチド、テトラヒドロピラン修飾ヌクレオチド、１，５－アンヒドロヘキシトール修飾ヌクレオチド、シクロヘキセニル修飾ヌクレオチド、５’－ホスホロチオエート基を含むヌクレオチド、５’－メチルホスホネート基を含むヌクレオチド、５’ホスフェートまたは５’ホスフェート模倣物を含むヌクレオチド、ビニルホスホネートを含むヌクレオチド、アデノシン－グリコール核酸（ＧＮＡ）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’－ホスフェートを含むヌクレオチド、２’－Ｏヘキサデシルヌクレオチド、２’－ホスフェートを含むヌクレオチド、シチジン－２’－ホスフェートヌクレオチド、グアノシン－２’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－シチジン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－アデノシン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－グアノシン－３’－ホスフェートヌクレオチド、２’－Ｏ－ヘキサデシル－ウリジン－３’－ホスフェートヌクレオチド、５’－ビニルホスホネート（ＶＰ）、２’－デオキシアデノシン－３’－ホスフェートヌクレオチド、２’－デオキシシチジン－３’－ホスフェートヌクレオチド、２’－デオキシグアノシン－３’－ホスフェートヌクレオチド、２’－デオキシチミジン－３’－ホスフェートヌクレオチド、２’－デオキシウリジンヌクレオチド、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に連結し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２０～２２のいずれか一項に記載の組成物。 At least one of the modified nucleotides is a deoxy-nucleotide, a 3'-terminal deoxy-thymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, a 2'-C-alkyl-modified nucleotide, a 2'-methoxyethyl-modified nucleotide, a 2'-O-alkyl-modified nucleotide, a morpholino nucleotide, Nucleotides, phosphoramidates, nucleotides containing unnatural bases, tetrahydropyran modified nucleotides, 1,5-anhydrohexitol modified nucleotides, cyclohexenyl modified nucleotides, nucleotides containing 5'-phosphorothioate groups, nucleotides containing 5'-methylphosphonate groups, nucleotides containing 5' phosphates or 5' phosphate mimetics, nucleotides containing vinyl phosphonates, nucleotides containing adenosine-glycol nucleic acid (GNA), nucleotides containing thymidine-glycol nucleic acid (GNA) S isomers, 2-hydroxymethyl- ... 2'-O-hexadecyl nucleotides, 2'-phosphate containing nucleotides, 2'-deoxythymidine-3'-phosphate containing nucleotides, 2'-deoxyguanosine-3'-phosphate containing nucleotides, 2'-O-hexadecyl nucleotides, 2'-phosphate containing nucleotides, cytidine-2'-phosphate nucleotides, guanosine-2'-phosphate nucleotides, 2'-O-hexadecyl-cytidine-3'-phosphate nucleotides, 2'-O-hexadecyl-adenosine-3'-phosphate nucleotides, 2'-O-hexadecyl-guanosine-3'-phosphate nucleotides 23. The composition of any one of claims 20 to 22, wherein the nucleotide is selected from the group consisting of nucleotides, 2'-O-hexadecyl-uridine-3'-phosphate nucleotides, 5'-vinylphosphonate (VP), 2'-deoxyadenosine-3'-phosphate nucleotides, 2'-deoxycytidine-3'-phosphate nucleotides, 2'-deoxyguanosine-3'-phosphate nucleotides, 2'-deoxythymidine-3'-phosphate nucleotides, 2' - deoxyuridine nucleotides, and terminal nucleotides linked to cholesteryl derivatives and dodecanoic acid bisdecylamide groups, and combinations thereof. ｄｓＲＮＡ剤の少なくとも１つが、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さらに含む、請求項２０～２３のいずれか一項に記載の組成物。 24. The composition of any one of claims 20-23 , wherein at least one of the dsRNA agents further comprises at least one phosphorothioate internucleotide linkage. 各ｄｓＲＮＡ剤の各鎖が独立に、３０ヌクレオチド長以下である、請求項２０～２４のいずれか一項に記載の組成物。 25. The composition of any one of claims 20-24 , wherein each strand of each dsRNA agent is independently 30 nucleotides or less in length. 少なくとも１つのｄｓＲＮＡ剤の少なくとも１つの鎖が独立に、少なくとも１ヌクレオチドの３’オーバーハングを含む、請求項２０～２５のいずれか一項に記載の組成物。 26. The composition of any one of claims 20-25 , wherein at least one strand of the at least one dsRNA agent independently comprises a 3' overhang of at least one nucleotide. 各ｄｓＲＮＡ剤の二本鎖領域が独立に、１５～３０ヌクレオチド対の長さである、請求項２０～２６のいずれか一項に記載の組成物。 27. The composition of any one of claims 20-26 , wherein the double-stranded region of each dsRNA agent is independently 15-30 nucleotide pairs in length. 各ｄｓＲＮＡ剤が、少なくとも１つの鎖における１つまたは複数の内部位置に独立にコンジュゲートされる１つまたは複数の親油性部分を含む、請求項２１～２７のいずれか一項に記載の組成物。 28. The composition of any one of claims 21-27 , wherein each dsRNA agent comprises one or more lipophilic moieties independently conjugated to one or more internal positions in at least one strand. . １つまたは複数の親油性部分のそれぞれが独立に、各鎖の５’端から数えて、センス鎖における位置４～８および１３～１８ならびにアンチセンス鎖における位置６～１０および１５～１８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される、請求項２８に記載の組成物。 Each of the one or more lipophilic moieties independently consists 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. 29. The composition of claim 28 , conjugated to one or more internal locations selected from the group. 親油性部分のそれぞれが独立に、脂肪族化合物、脂環式化合物、または多脂環式化合物である、請求項２８または２９に記載の組成物。 30. The composition of claim 28 or 29 , wherein each of the lipophilic moieties is independently an aliphatic, an alicyclic, or a polyalicyclic. 親油性部分のそれぞれが独立に、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３０に記載の組成物。 Each of the lipophilic moieties independently has 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. 31. The composition according to claim 30 , comprising: ｄｓＲＮＡ剤の少なくとも１つが、アンチセンス鎖の５’端にホスフェートまたはホスフェート模倣物をさらに含む、請求項２０～３１のいずれか一項に記載の組成物。 The composition of any one of claims 20 to 31 , wherein at least one of the dsRNA agents further comprises a phosphate or a phosphate mimetic at the 5'-end of the antisense strand. センス鎖ヌクレオチド配列５’－ＵＡＡＣＡＡＵＧＵＵＧＣＵＵＵＵＣＡＡＡＣ－３’（配列番号５）およびヌクレオチド配列５’－ＧＵＵＵＧＡＡＡＡＧＣＡＡＣＡＵＵＧＵＵＡＧＵ－３’（配列番号６）を含むアンチセンス鎖を含む第１のｄｓＲＮＡ剤、ならびにセンス鎖ヌクレオチド配列５’－ＡＣＵＧＵＡＣＡＧＵＣＵＡＡＡＡＵＧＵＣＡ－３’（配列番号７）およびヌクレオチド配列５’－ＵＧＡＣＡＵＵＵＵＡＧＡＣＵＧＵＡＣＡＧＵＧＧ－３’（配列番号８）を含むアンチセンス鎖を含む第２のｄｓＲＮＡ剤を含む、請求項２０～３２のいずれか一項に記載の組成物。 a first dsRNA agent comprising an antisense strand comprising a sense strand nucleotide sequence 5'-UAACAAUGUUGCUUUUCAAAC-3' (SEQ ID NO: 5) and a nucleotide sequence 5'-GUUUGAAAGCAACAUUGUUAGU-3' (SEQ ID NO: 6); and a sense strand nucleotide sequence 5' 33. Any one of claims 20 to 32 , comprising a second dsRNA agent comprising an antisense strand comprising '-ACUGUACAGUCUAAAAUGUCA-3' (SEQ ID NO: 7) and the nucleotide sequence 5'-UGACAUUUUAGACUGUACAGUGG-3' (SEQ ID NO: 8). The composition described in Section. 第１のｄｓＲＮＡ剤のセンス鎖が、センス鎖ヌクレオチド配列５’－ｕｓａｓａｃａ（Ａｈｄ）ＵｆｇＵｆＵｆＧｆｃｕｕｕｕｃａａｓａｓａ－３’（配列番号９）を含み、第１のｄｓＲＮＡ剤のアンチセンス鎖が、ヌクレオチド配列５’－ＶＰｕｓＵｆｓｕｕｇＡｆａａａｇｃａａＣｆａＵｆｕｇｕｕａｓｇｓｕ－３’（配列番号１０）を含み、第２のｄｓＲＮＡ剤のセンス鎖が、ヌクレオチド配列５’－ａｓｃｓｕｇｕ（Ａｈｄ）ＣｆａＧｆＵｆＣｆｕａａａａｕｇｕｓｃｓａ－３’（配列番号１１）を含み、第２のｄｓＲＮＡ剤のアンチセンス鎖が、ヌクレオチド配列５’－ＶＰｕｓＧｆｓａｃａＵｆｕｕｕａｇａｃＵｆｇＵｆａｃａｇｕｓｇｓｇ－３’（配列番号１２）を含み、
式中、ａ、ｇ、ｃおよびｕは、２’－Ｏ－メチル（２’－ＯＭｅ）Ａ、Ｇ、Ｃ、およびＵであり、Ａｆ、Ｇｆ、ＣｆおよびＵｆは、２’－フルオロＡ、Ｇ、ＣおよびＵであり、ｓは、ホスホロチオエート連結であり、（Ａｈｄ）は、２’－Ｏ－ヘキサデシル－アデノシン－３’－ホスフェートであり、ＶＰは、ビニル－ホスホネートである、請求項３３に記載の組成物。 the sense strand of the first dsRNA agent comprises the sense strand nucleotide sequence 5'-usasaca(Ahd)UfgUfUfGfcuuuucaasasa-3' (SEQ ID NO:9), the antisense strand of the first dsRNA agent comprises the nucleotide sequence 5'-VPusUfsuugAfaaagcaaCfaUfuguuasgsu-3' (SEQ ID NO:10), the sense strand of the second dsRNA agent comprises the nucleotide sequence 5'-ascsugu(Ahd)CfaGfUfCfuaaaauguscsa-3' (SEQ ID NO:11), and the antisense strand of the second dsRNA agent comprises the nucleotide sequence 5'-VPusGfsacaUfuuuagacUfgUfacagusgsg-3' (SEQ ID NO:12);
34. The composition of claim 33, wherein a, g, c and u are 2'-O-methyl (2'-OMe) A, G, C and U; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U; s is a phosphorothioate linkage; (Ahd) is 2'-O-hexadecyl-adenosine- 3' -phosphate; and VP is vinyl-phosphonate. 請求項２０～３４のいずれか一項に記載の組成物を含有する細胞。 A cell comprising the composition according to any one of claims 20 to 34 . コロナウイルスゲノムの発現を阻害するための医薬組成物である、請求項２０～３４のいずれか一項に記載の組成物。 The composition according to any one of claims 20 to 34 , which is a pharmaceutical composition for inhibiting the expression of a coronavirus genome. 細胞においてコロナウイルスゲノムの発現を阻害するインビトロ方法であって、
（ａ）細胞を、請求項１～１７のいずれか一項に記載のｄｓＲＮＡ剤、または請求項２０～３４のいずれか一項に記載の組成物、または請求項１９または３６に記載の医薬組成物と接触させること、ならびに
（ｂ）工程（ａ）において生成された細胞を、コロナウイルスゲノムの分解を得るのに十分な時間にわたって維持し、それにより、細胞におけるコロナウイルスゲノムの発現を阻害すること
を含む方法。 1. An in vitro method of inhibiting expression of a coronavirus genome in a cell, the method comprising:
(a) The cells are treated with a dsRNA agent according to any one of claims 1 to 17 , or a composition according to any one of claims 20 to 34 , or a pharmaceutical composition according to claims 19 or 36. (b) maintaining the cells produced in step (a) for a sufficient period of time to obtain degradation of the coronavirus genome, thereby inhibiting expression of the coronavirus genome in the cells; Methods that include. 細胞を、請求項１～１７のいずれか一項に記載の２つ以上のｄｓＲＮＡ剤と接触させる、請求項３７に記載の方法。 The method of claim 37 , wherein the cell is contacted with two or more dsRNA agents of any one of claims 1-17 . コロナウイルス感染を有する対象を処置するための医薬組成物であって、請求項１～１７のいずれか一項に記載のｄｓＲＮＡ剤、または請求項２０～３４のいずれか一項に記載の組成物、または請求項１９または３６に記載の医薬組成物を含む、医薬組成物。 A pharmaceutical composition for treating a subject with a coronavirus infection, the dsRNA agent according to any one of claims 1 to 17 or the composition according to any one of claims 20 to 34 , or a pharmaceutical composition according to claim 19 or 36 . 対象が、請求項１～１７のいずれか一項に記載の２つ以上のｄｓＲＮＡ剤を投与されるものである、請求項３９に記載の医薬組成物。 40. The pharmaceutical composition of claim 39 , wherein a subject is administered two or more dsRNA agents of any one of claims 1-17 . 対象がヒトである、請求項３９または４０に記載の医薬組成物。 41. The pharmaceutical composition of claim 39 or 40 , wherein the subject is a human. ｄｓＲＮＡの投与が、肺系投与である、請求項３９～４１のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 39 to 41 , wherein the administration of dsRNA is pulmonary administration. 肺系投与が、吸入によるか、または鼻内である、請求項４２に記載の医薬組成物。 43. The pharmaceutical composition of claim 42 , wherein pulmonary administration is by inhalation or intranasally. ｄｓＲＮＡ剤が、皮下投与のためのものである、請求項３９～４１のいずれか一項に記載の医薬組成物。 The pharmaceutical composition of any one of claims 39 to 41 , wherein the dsRNA agent is for subcutaneous administration.
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