JPWO2019226603A5 - - Google Patents
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- JPWO2019226603A5 JPWO2019226603A5 JP2020564923A JP2020564923A JPWO2019226603A5 JP WO2019226603 A5 JPWO2019226603 A5 JP WO2019226603A5 JP 2020564923 A JP2020564923 A JP 2020564923A JP 2020564923 A JP2020564923 A JP 2020564923A JP WO2019226603 A5 JPWO2019226603 A5 JP WO2019226603A5
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Description
本開示は以下の実施形態を含む。
実施形態１
２つ以上のプレマイクロＲＮＡ（プレｍｉＲＮＡ）に作動可能に連結されたｔＲＮＡを含むポリヌクレオチドであって、前記２つ以上のプレｍｉＲＮＡの各々が、前記プレｍｉＲＮＡに対して異種である挿入ＲＮＡ分子に作動可能に連結されている、ポリヌクレオチド。
実施形態２
前記ｔＲＮＡのステムループアンチコドンの全部または一部が、前記プレｍｉＲＮＡで置き換えられている、実施形態１に記載のポリヌクレオチド。
実施形態３
前記挿入ＲＮＡ分子が、
ａ）前記プレｍｉＲＮＡの５’末端、
ｂ）前記プレｍｉＲＮＡの３’末端、
ｃ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の５’、または
ｄ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の３’
に挿入される、近接する、または作動可能に連結される、実施形態１または２に記載のポリヌクレオチド。
実施形態４
前記ポリヌクレオチドが、約２７５ヌクレオチド以上、例えば、約２８０ヌクレオチド以上、例えば、約２９０ヌクレオチド以上、かつ約４００ヌクレオチドまでの長さである、実施形態１～３のいずれか一項に記載のポリヌクレオチド。
実施形態５
前記ｔＲＮＡが、セリン、ロイシン、グリシン、グルタメート、アスパルテート、グルタミン、アルギニン、システイン、リジン、メチオニン、アスパラギン、アラニン、ヒスチジン、イソロイシン、フェニルアラニン、プロリン、トリプトファン、チロシン、スレオニン、およびバリンからなる群から選択されるアミノ酸に由来するか、またはそれをコードするｔＲＮＡである、実施形態１～４のいずれか一項に記載のポリヌクレオチド。
実施形態６
前記ｔＲＮＡをコードするＲＮＡが、表８に示される配列番号３００～３５５に対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を有する５’ｔＲＮＡ配列および３’ｔＲＮＡ配列を含む、実施形態１～５のいずれか一項に記載のポリヌクレオチド。
実施形態７
前記ｔＲＮＡが、哺乳動物ｔＲＮＡ、例えばヒトｔＲＮＡである、実施形態１～６のいずれか一項に記載のポリヌクレオチド。
実施形態８
前記２つ以上のプレマイクロＲＮＡが、ヒトプレｍｉＲＮＡ分子に由来する、実施形態１～７のいずれか一項に記載のポリヌクレオチド。
実施形態９
前記２つ以上のプレｍｉＲＮＡが、プレｍｉＲ－３４ａ、プレｍｉＲ－１２４、プレｍｉＲ－１２９１、プレｍｉＲ－２００ｂ、プレｍｉＲ－２００ａ、プレｍｉＲ－１４１、プレｍｉＲ－４２９、プレｍｉＲ－１３３ａ、プレｌｅｔ－７ｃ、プレｍｉＲ－１２５ａ、プレｍｉＲ－３２８、プレｍｉＲ－１２６、プレｍｉＲ－２９８、プレｍｉＲ－１４８、プレｍｉＲ－１４４、プレｍｉＲ－１、プレｍｉＲ－１３３、プレｍｉＲ－８８８、プレｍｉＲ－６７７５、プレｍｉＲ－３７４、プレｍｉＲ－９２、プレｍｉＲ－１１８０、プレｍｉＲ－２１８、プレｍｉＲ－７、プレｍｉＲ－３７８、プレｍｉＲ－１７、プレｍｉＲ－１８ａ、プレｍｉＲ－２２、プレｍｉＲ－１２２、プレｍｉＲ－３０ｂ、プレｍｉＲ－４４９、プレｍｉＲ－５０６、プレｍｉＲ－９８、プレｍｉＲ－４４５８、プレｍｉＲ－２０６、プレｍｉＲ－５１９、プレｍｉＲ－９３、プレｍｉＲ－１０６、プレｍｉＲ－３７３、およびプレｍｉＲ－５２０からなる群から選択される、実施形態１～８のいずれか一項に記載のポリヌクレオチド。
実施形態１０
前記２つ以上のプレｍｉＲＮＡが、同じプレｍｉＲＮＡ分子に由来する、実施形態１～９のいずれか一項に記載のポリヌクレオチド。
実施形態１１
前記２つ以上のプレｍｉＲＮＡが、ヒトプレｍｉＲ－３４ａ分子に由来する、実施形態１０に記載のポリヌクレオチド。
実施形態１２
前記２つ以上のプレｍｉＲＮＡが、異なるプレｍｉＲＮＡ分子に由来する、実施形態１～９のいずれか一項に記載のポリヌクレオチド。
実施形態１３
前記挿入ＲＮＡが、非コードＲＮＡ（ｎｃＲＮＡ）、成熟マイクロＲＮＡ（ｍｉＲＮＡ）、低分子干渉ＲＮＡ（ｓｉＲＮＡ）、短いヘアピン型ＲＮＡ（ｓｈＲＮＡ）、Ｐｉｗｉ結合ＲＮＡ（ｐｉＲＮＡ）、核内低分子ＲＮＡ（ｓｎＲＮＡ）、核小体低分子ＲＮＡ（ｓｎｏＲＮＡ）、ガイドＲＮＡ（ｇＲＮＡ）、アンチセンスＲＮＡ（ａｓＲＮＡ）、低分子活性化ＲＮＡ（ｓａＲＮＡ）、触媒ＲＮＡ、リボスイッチ、ＲＮＡアプタマーからなる群から選択される、実施形態１～１２のいずれか一項に記載のポリヌクレオチド。
実施形態１４
前記挿入ＲＮＡが、少なくとも約１８個のヌクレオチドかつ最大約２００個までのヌクレオチドを有する、実施形態１～１３のいずれか一項に記載のポリヌクレオチド。
実施形態１５
前記挿入ＲＮＡが、少なくとも約１８個のヌクレオチドかつ最大約５０個までのヌクレオチドを有する、実施形態１４に記載のポリヌクレオチド。
実施形態１６
前記挿入ＲＮＡが、少なくとも約２０個のヌクレオチドかつ最大約２５個までのヌクレオチドを有する、実施形態１４に記載のポリヌクレオチド。
実施形態１７
前記挿入ＲＮＡが、成熟ｍｉＲＮＡである、実施形態１～１６のいずれか一項に記載のポリヌクレオチド。
実施形態１８
前記挿入ＲＮＡが、ｌｅｔ－７ｃ、ｍｉＲ－２９８、ｍｉＲ－２１６、ｍｉＲ－３４ａ、ｍｉＲ－１２４、ｍｉＲ－３２８、ｍｉＲ－１４４、ｍｉＲ－１２６、ｍｉＲ－１６、ｍｉＲ－１８、ｍｉＲ－１２５ａ、ｍｉＲ－１９５、ｍｉＲ－１９９ａ、ｍｉＲ－２００、ｍｉＲ－２２４、ｍｉＲ－１２９１、ｍｉＲ－４２９、ｍｉＲ－１４８、ｍｉＲ－１４４、ｍｉＲ－１、ｍｉＲ－１３３、ｍｉＲ－８８８、ｍｉＲ－６７７５、ｍｉＲ－３７４、ｍｉＲ－９２、ｍｉＲ－１１８０、ｍｉＲ－２１８、ｍｉＲ－７、ｍｉＲ－３７８、ｍｉＲ－１７、ｍｉＲ－１８ａ、ｍｉＲ－２２、ｍｉＲ－１２２、ｍｉＲ－３０ｂ、ｍｉＲ－４４９、ｍｉＲ－５０６、ｍｉＲ－９８、ｍｉＲ－４４５８、ｍｉＲ－２０６、ｍｉＲ－５１９、ｍｉＲ－９３、ｍｉＲ－１０６、ｍｉＲ－３７３、およびｍｉＲ－５２０からなる群から選択される２つ以上の成熟ｍｉＲＮＡを含む、実施形態１～１７のいずれか一項に記載のポリヌクレオチド。
実施形態１９
前記２つ以上のプレｍｉＲＮＡにおける前記挿入ＲＮＡが同じである、実施形態１～１８のいずれか一項に記載のポリヌクレオチド。
実施形態２０
前記２つ以上のプレｍｉＲＮＡにおける前記挿入ＲＮＡが異なる、実施形態１～１８のいずれか一項に記載のポリヌクレオチド。
実施形態２１
前記挿入ＲＮＡが、ｌｅｔ－７ｃ、ｍｉＲ－１２９１、ｍｉＲ－２００、ｍｉＲ－９２、ｍｉＲ－３４ａおよびｍｉＲ－１２４からなる群から選択される、実施形態１～２０のいずれか一項に記載のポリヌクレオチド。
実施形態２２
前記挿入ＲＮＡが、ｍｉＲ－１２９１、ｍｉＲ－３４、ｍｉＲ－１２４、ｍｉＲ－２００、およびｍｉＲ－２１６からなる群から選択される成熟ｍｉＲＮＡである、実施形態１～２０のいずれか一項に記載のポリヌクレオチド。
実施形態２３
前記挿入ＲＮＡが、ｌｅｔ－７ｃ、ｍｉＲ－２９８、ｍｉＲ－２１６、ｍｉＲ－１２４、ｍｉＲ－３２８、ｍｉＲ－１４４、ｍｉＲ－１２６、ｍｉＲ－１６、ｍｉＲ－１８、ｍｉＲ－１２５ａ、ｍｉＲ－１９５、ｍｉＲ－１９９ａ、ｍｉＲ－２００、およびｍｉＲ－２２４からなる群から選択される成熟ｍｉＲＮＡである、実施形態１～２０のいずれか一項に記載のポリヌクレオチド。
実施形態２４
さらに、前記ｔＲＮＡおよび／またはプレｍｉＲＮＡが、１つ以上のアプタマー、低分子活性化ＲＮＡ（ｓａＲＮＡ）、または触媒ＲＮＡに作動可能に連結されている、実施形態１～２３のいずれか一項に記載のポリヌクレオチド。
実施形態２５
前記アプタマー、ｓａＲＮＡまたは触媒ＲＮＡが、
ａ）前記プレｍｉＲＮＡの５’末端、
ｂ）前記プレｍｉＲＮＡの３’末端、
ｃ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の５、または
ｄ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の３’
に挿入される、近接する、または作動可能に連結される、実施形態２４に記載のポリヌクレオチド。
実施形態２６
前記アプタマーが、セフェデックス、ＥｐＣＡＭ、ＶＥＧＦ、ｆｍｓ関連チロシンキナーゼ１（ＦＬＴ１）、テオフィリン、マラカイトグリーン、ＨＣＣ－２２－５、ケラチン２３（ＫＲＴ２３）、アルファ２－ＨＳ糖タンパク質（ＡＨＳＧ）、フェリチン軽鎖（ＦＴＬ）、ＭＡＧＥ－Ａ１、ＭＡＧＥ－Ａ３／４、ＮＹ－ＥＳＯ－１、１４－３－３ζ、ｃ－Ｍｙｃ、ＭＤＭ２、ＮＰＭ１、ｐ１６、ｐ５３、サイクリンＢ１、ＫＩＦ２０Ａ、ＭＵＣ１、ＣＡ１９－９、ＤＵ－ＰＡＮ－２、ＴＡＧ－７２、カドヘリン３（ＣＤＨ３）／Ｐ－カドヘリン、ＳｉＳｏ細胞で発現する受容体結合がん抗原（ＲＣＡＳ１）、およびＳＣ６からなる群から選択される標的抗原に結合するものである、実施形態２４～２５のいずれか一項に記載のポリヌクレオチド。
実施形態２７
前記アプタマーが、配列番号３５６～３５９のうちの１つに対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を含む核酸配列を含む、実施形態２４～２６のいずれか一項に記載のポリヌクレオチド。
実施形態２８
前記ポリヌクレオチドが、配列番号１８３～２１０、２６５～２８８および２９６～２９８のうちのいずれか１つに対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を含む、実施形態１～２７のいずれか一項に記載のポリヌクレオチド。
実施形態２９
プレｍｉＲＮＡに作動可能に連結されたｔＲＮＡを含むポリヌクレオチドであって、前記ポリヌクレオチドが、配列番号８５～１８２および２１１～２６４のうちのいずれか１つに対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％、または１００％の配列同一性を含む、ポリヌクレオチド。
実施形態３０
挿入ＲＮＡ分子を含むプレｍｉＲＮＡに作動可能に連結されたヒトｔＲＮＡを含むポリヌクレオチドであって、例えば、前記挿入ＲＮＡ分子が、前記プレｍｉＲＮＡに対して異種であり、前記ポリヌクレオチドが、配列番号２８９～２９５のうちのいずれか１つに対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を含む、ポリヌクレオチド。
実施形態３１
前記ｔＲＮＡのステムループアンチコドンの全部または一部が、前記プレｍｉＲＮＡで置き換えられている、実施形態３０に記載のポリヌクレオチド。
実施形態３２
前記ポリヌクレオチドが、約１５０ヌクレオチド以上、例えば、約１６０ヌクレオチド以上、例えば、約１７０ヌクレオチド以上、例えば、約１８０ヌクレオチド以上、かつ約２３０ヌクレオチドまでの長さである、実施形態３０～３１のいずれか一項に記載のポリヌクレオチド。
実施形態３３
前記ｔＲＮＡが、セリン、ロイシン、グリシン、グルタメート、アスパルテート、グルタミン、アルギニン、システイン、リジン、メチオニン、アスパラギン、アラニン、ヒスチジン、イソロイシン、フェニルアラニン、プロリン、トリプトファン、チロシン、スレオニン、およびバリンからなる群から選択されるアミノ酸に由来するか、またはそれをコードするｔＲＮＡである、実施形態３０～３２のいずれか一項に記載のポリヌクレオチド。
実施形態３４
前記ｔＲＮＡをコードする前記ＲＮＡが、表８に提供される配列番号３００～３５５に対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を有する５’ｔＲＮＡ配列および３’ｔＲＮＡ配列を含む、実施形態３０～３３のいずれか一項に記載のポリヌクレオチド。
実施形態３５
前記ｔＲＮＡが、哺乳動物ｔＲＮＡ、例えばヒトｔＲＮＡである、実施形態３０～３４のいずれか一項に記載のポリヌクレオチド。
実施形態３６
前記挿入ＲＮＡが、非コードＲＮＡ（ｎｃＲＮＡ）、成熟マイクロＲＮＡ（ｍｉＲＮＡ）、低分子干渉ＲＮＡ（ｓｉＲＮＡ）、短いヘアピン型ＲＮＡ（ｓｈＲＮＡ）、Ｐｉｗｉ結合ＲＮＡ（ｐｉＲＮＡ）、核内低分子ＲＮＡ（ｓｎＲＮＡ）、核小体低分子ＲＮＡ（ｓｎｏＲＮＡ）、ガイドＲＮＡ（ｇＲＮＡ）、アンチセンスＲＮＡ（ａｓＲＮＡ）、低分子活性化ＲＮＡ（ｓａＲＮＡ）、触媒ＲＮＡ、リボスイッチ、およびＲＮＡアプタマーからなる群から選択される、実施形態３０～３５のいずれか一項に記載のポリヌクレオチド。
実施形態３７
前記挿入ＲＮＡが、少なくとも約１８個のヌクレオチドかつ最大約２００個までのヌクレオチドを有する、実施形態３０～３６のいずれか一項に記載のポリヌクレオチド。
実施形態３８
前記挿入ＲＮＡが、少なくとも約１８個のヌクレオチドかつ最大約５０個までのヌクレオチドを有する、実施形態３７に記載のポリヌクレオチド。
実施形態３９
前記挿入ＲＮＡが、少なくとも約２０個のヌクレオチドかつ最大約２５個までのヌクレオチドを有する、実施形態３７に記載のポリヌクレオチド。
実施形態４０
前記挿入ＲＮＡが、成熟ｍｉＲＮＡである、実施形態３０～３９のいずれか一項に記載のポリヌクレオチド。
実施形態４１
前記挿入ＲＮＡが、ｌｅｔ－７ｃ、ｍｉＲ－２９８、ｍｉＲ－２１６、ｍｉＲ－３４ａ、ｍｉＲ－１２４、ｍｉＲ－３２８、ｍｉＲ－１４４、ｍｉＲ－１２６、ｍｉＲ－１６、ｍｉＲ－１８、ｍｉＲ－１２５ａ、ｍｉＲ－１９５、ｍｉＲ－１９９ａ、ｍｉＲ－２００、ｍｉＲ－２２４、ｍｉＲ－１２９１、ｍｉＲ－４２９、ｍｉＲ－１４８、ｍｉＲ－１４４、ｍｉＲ－１、ｍｉＲ－１３３、ｍｉＲ－８８８、ｍｉＲ－６７７５、ｍｉＲ－３７４、ｍｉＲ－９２、ｍｉＲ－１１８０、ｍｉＲ－２１８、ｍｉＲ－７、ｍｉＲ－３７８、ｍｉＲ－１７、ｍｉＲ－１８ａ、ｍｉＲ－２２、ｍｉＲ－１２２、ｍｉＲ－３０ｂ、ｍｉＲ－４４９、ｍｉＲ－５０６、ｍｉＲ－９８、ｍｉＲ－４４５８、ｍｉＲ－２０６、ｍｉＲ－５１９、ｍｉＲ－９３、ｍｉＲ－１０６、ｍｉＲ－３７３、およびｍｉＲ－５２０からなる群から選択される成熟ｍｉＲＮＡである、実施形態３０～４０のいずれか一項に記載のポリヌクレオチド。
実施形態４２
さらに、前記ｔＲＮＡおよび／またはプレｍｉＲＮＡが、アプタマー、低分子活性化ＲＮＡ（ｓａＲＮＡ）、または触媒ＲＮＡに作動可能に連結されている、実施形態３０～４１のいずれか一項に記載のポリヌクレオチド。
実施形態４３
前記アプタマー、ｓａＲＮＡまたは触媒ＲＮＡが、
ａ）前記プレｍｉＲＮＡの５’末端、
ｂ）前記プレｍｉＲＮＡの３’末端、
ｃ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の５’、または
ｄ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の３’
に挿入される、近接する、または作動可能に連結される、実施形態４２に記載のポリヌクレオチド。
実施形態４４
前記アプタマーが、セフェデックス、ＥｐＣＡＭ、ＶＥＧＦ、ｆｍｓ関連チロシンキナーゼ１（ＦＬＴ１）、テオフィリン、マラカイトグリーン、ＨＣＣ－２２－５、ケラチン２３（ＫＲＴ２３）、アルファ２－ＨＳ糖タンパク質（ＡＨＳＧ）、フェリチン軽鎖（ＦＴＬ）、ＭＡＧＥ－Ａ１、ＭＡＧＥ－Ａ３／４、ＮＹ－ＥＳＯ－１、１４－３－３ζ、ｃ－Ｍｙｃ、ＭＤＭ２、ＮＰＭ１、ｐ１６、ｐ５３、サイクリンＢ１、ＫＩＦ２０Ａ、ＭＵＣ１、ＣＡ１９－９、ＤＵ－ＰＡＮ－２、ＴＡＧ－７２、カドヘリン３（ＣＤＨ３）／Ｐ－カドヘリン、ＳｉＳｏ細胞で発現する受容体結合がん抗原（ＲＣＡＳ１）、およびＳＣ６からなる群から選択される標的抗原に結合するものである、実施形態３０～４３のいずれか一項に記載のポリヌクレオチド。
実施形態４５
前記アプタマーが、配列番号３５６～３５９のうちの１つに対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を含む核酸配列を含む、実施形態３０～４４のいずれか一項に記載のポリヌクレオチド。
実施形態４６
配列番号８５～２９８に対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を含む、実施形態１～４５のいずれか一項に記載のポリヌクレオチド。
実施形態４７
前記プレｍｉＲＮＡが、天然由来または人工由来である、実施形態１～４６のいずれか一項に記載のポリヌクレオチド。
実施形態４８
前記ポリヌクレオチドが、哺乳動物に対して実質的に非免疫原性である、実施形態１～４７のいずれか一項に記載のポリヌクレオチド。
実施形態４９
実施形態１～４８のいずれか一項に記載のポリヌクレオチドを含む発現カセット。
実施形態５０
実施形態１～４８のいずれか一項に記載のポリヌクレオチドまたは実施形態４９に記載の発現カセットを含む、リポソームまたはナノ粒子。
実施形態５１
実施形態１～４８のいずれか一項に記載のポリヌクレオチドまたは実施形態４９に記載の発現カセットを含む、ウイルスベクター。
実施形態５２
前記リポソームが、ポリエチレンイミン（ＰＥＩ）と複合体を形成した実施形態１～４８のいずれか一項に記載のポリヌクレオチドを含む内部コアと、外部脂質二重層とを含む、実施形態５０に記載のリポソームまたはナノ粒子。
実施形態５３
前記内部コアが、例えば約１０，０００ダルトンの分子量を有する、リポソーム分岐ポリエチレンイミン（ＰＥＩ）ポリプレックス（ＬＰＰ）を含む、実施形態５０～５２のいずれか一項に記載のリポソームまたはナノ粒子。
実施形態５４
前記外部脂質二重層が、１，２－ジ－Ｏ－オクタデセニル－３－トリメチルアンモニウムプロパン（ＤＯＴＭＡ）、コレステロールおよび１，２－ジミリストイル－ｓｎ－グリセロール、メトキシポリエチレングリコール（ＤＭＧ－ＰＥＧ２０００）の混合物を含む、実施形態５０～５３のいずれか一項に記載のリポソームまたはナノ粒子。
実施形態５５
実施形態１～４８のいずれか一項に記載のポリヌクレオチドまたは実施形態４９に記載の発現カセットまたは実施形態５０～５４のいずれか一項に記載のリポソームもしくはナノ粒子でトランスフェクトまたは形質転換された、宿主細胞。
実施形態５６
前記宿主細胞が、原核細胞または真核細胞である、実施形態５５に記載の宿主細胞。
実施形態５７
前記宿主細胞が、細菌細胞、哺乳動物細胞、昆虫細胞または植物細胞から選択される、実施形態５５または５６に記載の宿主細胞。
実施形態５８
必要とする対象において、がんの成長、増殖、および／または進行を予防、緩和、低減、逆転および／または阻害する方法であって、実施形態１～４８のいずれか一項に記載のポリヌクレオチドまたは実施形態４９に記載の発現カセットまたは実施形態５０～５４のいずれか一項に記載のリポソーム、ナノ粒子もしくはウイルスベクターを前記対象に投与することを含む、方法。
実施形態５９
前記がんが、乳がん、リンパ腫、結腸直腸がん、肝細胞がん、膵臓がん、前立腺がん、および肺がんからなる群から選択される、実施形態５８に記載の方法。
実施形態６０
前記ポリヌクレオチドが、ｌｅｔ－７ｃ、ｍｉＲ－２９８、ｍｉＲ－２１６、ｍｉＲ－３４ａ、ｍｉＲ－１２４、ｍｉＲ－３２８、ｍｉＲ－１４４、ｍｉＲ－１２６、ｍｉＲ－１６、ｍｉＲ－１８、ｍｉＲ－１２５ａ、ｍｉＲ－１９５、ｍｉＲ－１９９ａ、ｍｉＲ－２００、ｍｉＲ－２２４、ｍｉＲ－１２９１、ｍｉＲ－４２９、ｍｉＲ－１４８、ｍｉＲ－１４４、ｍｉＲ－１、ｍｉＲ－１３３、ｍｉＲ－８８８、ｍｉＲ－６７７５、ｍｉＲ－３７４、ｍｉＲ－９２、ｍｉＲ－１１８０、ｍｉＲ－２１８、ｍｉＲ－７、ｍｉＲ－３７８、ｍｉＲ－１７、ｍｉＲ－１８ａ、ｍｉＲ－２２、ｍｉＲ－１２２、ｍｉＲ－３０ｂ、ｍｉＲ－４４９、ｍｉＲ－５０６、ｍｉＲ－９８、ｍｉＲ－４４５８、ｍｉＲ－２０６、ｍｉＲ－５１９、ｍｉＲ－９３、ｍｉＲ－１０６、ｍｉＲ－３７３、およびｍｉＲ－５２０からなる群から選択される１つ以上の成熟ｍｉＲＮＡを含む、実施形態５８または５９に記載の方法。
実施形態６１
前記がんが、肺がんであり、前記ポリヌクレオチドが、ｍｉＲ－３４ａおよびｍｉＲ－１２４からなる群から選択される１つ以上の成熟ｍｉＲＮＡを含む、実施形態５８～６０のいずれか一項に記載の方法。
実施形態６２
前記がんが、膵臓がんであり、前記ポリヌクレオチドが、ｍｉＲ－１２９１、ｍｉＲ－３４、ｍｉＲ－１２４、ｍｉＲ－２００、およびｍｉＲ－２１６からなる群から選択される１つ以上の成熟ｍｉＲＮＡを含む、実施形態５８～６０のいずれか一項に記載の方法。
実施形態６３
前記がんが、肝細胞がんであり、前記ポリヌクレオチドが、ｌｅｔ－７ｃ、ｍｉＲ－２９８、ｍｉＲ－２１６、ｍｉＲ－１２４、ｍｉＲ－３２８、ｍｉＲ－１４４、ｍｉＲ－１２６、ｍｉＲ－１６、ｍｉＲ－１８、ｍｉＲ－１２５ａ、ｍｉＲ－１９５、ｍｉＲ－１９９ａ、ｍｉＲ－２００、およびｍｉＲ－２２４からなる群から選択される１つ以上の成熟ｍｉＲＮＡを含む、実施形態５８～６０のいずれか一項に記載の方法。
実施形態６４
前記ポリヌクレオチド、リポソームまたはナノ粒子が、静脈内、動脈内、腹腔内、腹腔内、肺内、肝内、皮下または腫瘍内から選択される経路を介して投与される、実施形態５８～６３のいずれか一項に記載の方法。
実施形態６５
前記ポリヌクレオチド、リポソームまたはナノ粒子の治療レジメンが、複数回、例えば、毎日、毎週、隔週、毎月、例えば所定のまたは所望のエンドポイントに達するまで、投与される、実施形態５８～６４のいずれか一項に記載の方法。
実施形態６６
前記対象が、がんの症状を示している、例えば、１つ以上の腫瘍を有している、実施形態５８～６５のいずれか一項に記載の方法。
実施形態６７
前記対象が、寛解状態にあり、腫瘍を再発症するリスクがある、実施形態５８～６５のいずれか一項に記載の方法。
実施形態６８
１つ以上の化学療法剤または抗がん剤の同時投与をさらに含む、実施形態５８～６７のいずれか一項に記載の方法。
実施形態６９
前記対象が、投与前に１つ以上のｍｉＲＮＡの過剰発現または過少発現について試験される、実施形態５８～６８のいずれか一項に記載の方法。
実施形態７０
配列番号８５～２９８に対して少なくとも約９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％または１００％の配列同一性を有する１つ以上のハイブリッドｔＲＮＡ／プレｍｉＲＮＡ分子を前記対象に投与することを含む、実施形態５８～６９のいずれか一項に記載の方法。
実施形態７１
実施形態１～４８のいずれか一項に記載のポリヌクレオチドまたは実施形態４９に記載の発現カセット、実施形態５０～５４のいずれか一項に記載のリポソーム、ナノ粒子もしくはウイルスベクター、および／または実施形態５５～５７のいずれか一項に記載の宿主細胞を含む、キット。
本明細書に記載の実施例および実施形態は、例示のみを目的としており、それに照らして種々の改変または変更が当業者に提案され、本出願の趣旨および範囲ならびに添付の特許請求の範囲に含まれるべきであることが理解されよう。本明細書で引用したすべての刊行物、特許、および特許出願は、あらゆる目的で、それらの全体が参照により本明細書に組み込まれる。
The disclosure includes the following embodiments:
Embodiment 1
An inserted RNA molecule comprising a tRNA operably linked to two or more premiRNAs, wherein each of the two or more premiRNAs is heterologous to the premiRNA. A polynucleotide that is operably linked to.
Embodiment 2
The polynucleotide according to embodiment 1, wherein all or part of the stem-loop anticodon of the tRNA has been replaced with the premiRNA.
Embodiment 3
The inserted RNA molecule
a) The 5'end of the premiRNA,
b) The 3'end of the premiRNA,
c) 5'or at the dicer or RNase cleavage site of the premiRNA, or
d) 3'at the dicer or RNase cleavage site of the premiRNA
The polynucleotide according to embodiment 1 or 2, which is inserted into, adjacent to, or operably linked to.
Embodiment 4
The polynucleotide according to any one of embodiments 1 to 3, wherein the polynucleotide is about 275 nucleotides or more, for example, about 280 nucleotides or more, for example, about 290 nucleotides or more, and has a length of up to about 400 nucleotides. ..
Embodiment 5
The tRNA is selected from the group consisting of serine, leucine, glycine, glutamate, aspartate, glutamine, arginine, cysteine, lysine, methionine, asparagine, alanine, histidine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, threonine, and valine. The polynucleotide according to any one of embodiments 1 to 4, which is a tRNA derived from or encoding the amino acid to be used.
Embodiment 6
The RNA encoding the tRNA is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, relative to SEQ ID NOs: 300-355 shown in Table 8. The polynucleotide according to any one of embodiments 1 to 5, comprising a 5'tRNA sequence and a 3'tRNA sequence having 99% or 100% sequence identity.
Embodiment 7
The polynucleotide according to any one of Embodiments 1 to 6, wherein the tRNA is a mammalian tRNA, for example, a human tRNA.
8th embodiment
The polynucleotide according to any one of embodiments 1 to 7, wherein the two or more premicroRNAs are derived from a human premiRNA molecule.
Embodiment 9
The two or more premiRNAs are premiR-34a, premiR-124, premiR-1291, premiR-200b, premiR-200a, premiR-141, premiR-429, premiR-133a, pre. let-7c, pre miR-125a, pre miR-328, pre miR-126, pre miR-298, pre miR-148, pre miR-144, pre miR-1, pre miR-133, pre miR-888, pre miR-6775, pre miR-374, pre miR-92, pre miR-1180, pre miR-218, pre miR-7, pre miR-378, pre miR-17, pre miR-18a, pre miR-22, pre miR-122, pre miR-30b, pre miR-449, pre miR-506, pre miR-98, pre miR-4458, pre miR-206, pre miR-519, pre miR-93, pre miR-106, pre The polynucleotide according to any one of embodiments 1 to 8, selected from the group consisting of miR-373 and premiR-520.
Embodiment 10
The polynucleotide according to any one of embodiments 1 to 9, wherein the two or more premiRNAs are derived from the same premiRNA molecule.
Embodiment 11
The polynucleotide according to embodiment 10, wherein the two or more premiRNAs are derived from a human premiR-34a molecule.
Embodiment 12
The polynucleotide according to any one of embodiments 1 to 9, wherein the two or more premiRNAs are derived from different premiRNA molecules.
Embodiment 13
The inserted RNA includes non-coding RNA (ncRNA), mature microRNA (miRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), Piwi binding RNA (piRNA), and nuclear small RNA (snRNA). , Selected from the group consisting of nuclear body small molecule RNA (snoRNA), guide RNA (gRNA), antisense RNA (asRNA), small molecule activated RNA (saRNA), catalytic RNA, riboswitch, RNA aptamer. The polynucleotide according to any one of forms 1 to 12.
Embodiment 14
The polynucleotide according to any one of embodiments 1 to 13, wherein the inserted RNA has at least about 18 nucleotides and up to about 200 nucleotides.
Embodiment 15
13. The polynucleotide according to embodiment 14, wherein the inserted RNA has at least about 18 nucleotides and up to about 50 nucleotides.
Embodiment 16
13. The polynucleotide according to embodiment 14, wherein the inserted RNA has at least about 20 nucleotides and up to about 25 nucleotides.
Embodiment 17
The polynucleotide according to any one of embodiments 1 to 16, wherein the inserted RNA is a mature miRNA.
Embodiment 18
The inserted RNAs are let-7c, miR-298, miR-216, miR-34a, miR-124, miR-328, miR-144, miR-126, miR-16, miR-18, miR-125a, miR. -195, miR-199a, miR-200, miR-224, miR-1291, miR-429, miR-148, miR-144, miR-1, miR-133, miR-888, miR-6775, miR-374 , MiR-92, miR-1180, miR-218, miR-7, miR-378, miR-17, miR-18a, miR-22, miR-122, miR-30b, miR-449, miR-506, miR Embodiment 1 comprising two or more mature miRNAs selected from the group consisting of -98, miR-4458, miR-206, miR-519, miR-93, miR-106, miR-373, and miR-520. The polynucleotide according to any one of 17 to 17.
Embodiment 19
The polynucleotide according to any one of embodiments 1 to 18, wherein the inserted RNA in the two or more premiRNAs is the same.
20th embodiment
The polynucleotide according to any one of embodiments 1 to 18, wherein the inserted RNA in the two or more premiRNAs is different.
21st embodiment
The poly according to any one of embodiments 1 to 20, wherein the inserted RNA is selected from the group consisting of let-7c, miR-1291, miR-200, miR-92, miR-34a and miR-124. nucleotide.
Embodiment 22
13. Polynucleotide.
23rd Embodiment
The inserted RNAs are let-7c, miR-298, miR-216, miR-124, miR-328, miR-144, miR-126, miR-16, miR-18, miR-125a, miR-195, miR. The polynucleotide according to any one of embodiments 1 to 20, which is a mature miRNA selected from the group consisting of -199a, miR-200, and miR-224.
Embodiment 24
Further, according to any one of embodiments 1 to 23, wherein the tRNA and / or premiRNA is operably linked to one or more aptamers, small activation RNAs (saRNAs), or catalytic RNAs. Polynucleotide.
25th embodiment
The aptamer, saRNA or catalytic RNA
a) The 5'end of the premiRNA,
b) The 3'end of the premiRNA,
c) 5 of the dicer or RNase cleavage site of the premiRNA, or
d) 3'at the dicer or RNase cleavage site of the premiRNA
24. The polynucleotide according to embodiment 24, which is inserted into, in close proximity to, or operably linked to.
Embodiment 26
The antigens are cefedex, EpCAM, VEGF, fms-related tyrosine kinase 1 (FLT1), theophylline, malakite green, HCC-22-5, keratin 23 (KRT23), alpha 2-HS glycoprotein (AHSG), ferritin light chain. (FTL), MAGE-A1, MAGE-A3 / 4, NY-ESO-1, 14-3-3ζ, c-Myc, MDM2, NPM1, p16, p53, Cyclone B1, KIF20A, MUC1, CA19-9, DU -It binds to a target antigen selected from the group consisting of PAN-2, TAG-72, cadherin 3 (CDH3) / P-cadherin, receptor-binding cancer antigen (RCAS1) expressed in SiSo cells, and SC6. A polynucleotide according to any one of embodiments 24 to 25.
Embodiment 27
The aptamer is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 with respect to one of SEQ ID NOs: 356-359. The polynucleotide according to any one of embodiments 24-26, comprising a nucleic acid sequence comprising% sequence identity.
Embodiment 28
The polynucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96% with respect to any one of SEQ ID NOs: 183 to 210, 265 to 288 and 296 to 298. , 97%, 98%, 99% or 100% of the polynucleotide according to any one of embodiments 1-27.
Embodiment 29
A polynucleotide comprising a tRNA operably linked to a premiRNA, wherein the polynucleotide is at least about 90%, 91%, relative to any one of SEQ ID NOs: 85-182 and 211-264. A polynucleotide comprising 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.
30th embodiment
A polynucleotide comprising a human tRNA operably linked to a premiRNA comprising an inserted RNA molecule, eg, the inserted RNA molecule is heterologous to the premiRNA and the polynucleotide is SEQ ID NO: 289. Sequence identity of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% for any one of ~ 295. Containing, polynucleotides.
Embodiment 31
30. The polynucleotide according to embodiment 30, wherein all or part of the stem-loop anticodon of the tRNA has been replaced with the premiRNA.
Embodiment 32
Any of embodiments 30-31, wherein the polynucleotide is about 150 nucleotides or more, eg, about 160 nucleotides or more, eg, about 170 nucleotides or more, eg, about 180 nucleotides or more, and up to about 230 nucleotides in length. The polynucleotide according to one item.
Embodiment 33
The tRNA is selected from the group consisting of serine, leucine, glycine, glutamate, aspartate, glutamine, arginine, cysteine, lysine, methionine, asparagine, alanine, histidine, isoleucine, phenylalanine, proline, tryptophan, tyrosine, threonine, and valine. 13. The polynucleotide according to any one of embodiments 30-32, which is a tRNA derived from or encodes an amino acid thereof.
Embodiment 34
The RNA encoding the tRNA is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 relative to SEQ ID NOs: 300-355 provided in Table 8. The polynucleotide according to any one of embodiments 30-33, comprising a 5'tRNA sequence and a 3'tRNA sequence having%, 99% or 100% sequence identity.
Embodiment 35
The polynucleotide according to any one of embodiments 30 to 34, wherein the tRNA is a mammalian tRNA, eg, a human tRNA.
Embodiment 36
The inserted RNA includes non-coding RNA (ncRNA), mature microRNA (miRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), Piwi binding RNA (piRNA), and nuclear small RNA (snRNA). , Selected from the group consisting of nuclear body small molecule RNA (snoRNA), guide RNA (gRNA), antisense RNA (asRNA), small molecule activated RNA (saRNA), catalytic RNA, riboswitch, and RNA aptamer. The polynucleotide according to any one of embodiments 30 to 35.
Embodiment 37
The polynucleotide according to any one of embodiments 30 to 36, wherein the inserted RNA has at least about 18 nucleotides and up to about 200 nucleotides.
Embodiment 38
13. The polynucleotide according to embodiment 37, wherein the inserted RNA has at least about 18 nucleotides and up to about 50 nucleotides.
Embodiment 39
13. The polynucleotide according to embodiment 37, wherein the inserted RNA has at least about 20 nucleotides and up to about 25 nucleotides.
Embodiment 40
The polynucleotide according to any one of embodiments 30 to 39, wherein the inserted RNA is a mature miRNA.
Embodiment 41
The inserted RNAs are let-7c, miR-298, miR-216, miR-34a, miR-124, miR-328, miR-144, miR-126, miR-16, miR-18, miR-125a, miR. -195, miR-199a, miR-200, miR-224, miR-1291, miR-429, miR-148, miR-144, miR-1, miR-133, miR-888, miR-6775, miR-374 , MiR-92, miR-1180, miR-218, miR-7, miR-378, miR-17, miR-18a, miR-22, miR-122, miR-30b, miR-449, miR-506, miR Any of embodiments 30-40, which is a mature miRNA selected from the group consisting of -98, miR-4458, miR-206, miR-519, miR-93, miR-106, miR-373, and miR-520. The polynucleotide according to one item.
42nd embodiment
The polynucleotide according to any one of embodiments 30-41, wherein the tRNA and / or premiRNA is operably linked to an aptamer, small activation RNA (saRNA), or catalytic RNA.
Embodiment 43
The aptamer, saRNA or catalytic RNA
a) The 5'end of the premiRNA,
b) The 3'end of the premiRNA,
c) 5'or at the dicer or RNase cleavage site of the premiRNA, or
d) 3'at the dicer or RNase cleavage site of the premiRNA
42. The polynucleotide according to embodiment 42, which is inserted into, adjacent to, or operably linked to.
Embodiment 44
The antigens are cefedex, EpCAM, VEGF, fms-related tyrosine kinase 1 (FLT1), theophylline, malakite green, HCC-22-5, keratin 23 (KRT23), alpha 2-HS glycoprotein (AHSG), ferritin light chain. (FTL), MAGE-A1, MAGE-A3 / 4, NY-ESO-1, 14-3-3ζ, c-Myc, MDM2, NPM1, p16, p53, Cyclone B1, KIF20A, MUC1, CA19-9, DU -It binds to a target antigen selected from the group consisting of PAN-2, TAG-72, cadherin 3 (CDH3) / P-cadherin, receptor-binding cancer antigen (RCAS1) expressed in SiSo cells, and SC6. The polynucleotide according to any one of embodiments 30 to 43.
Embodiment 45
The aptamer is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 with respect to one of SEQ ID NOs: 356-359. The polynucleotide according to any one of embodiments 30-44, comprising a nucleic acid sequence comprising% sequence identity.
Embodiment 46
Implementations comprising at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs: 85-298. The polynucleotide according to any one of forms 1 to 45.
Embodiment 47
The polynucleotide according to any one of embodiments 1 to 46, wherein the premiRNA is of natural or artificial origin.
Embodiment 48
The polynucleotide according to any one of embodiments 1 to 47, wherein the polynucleotide is substantially non-immunogenic to a mammal.
Embodiment 49
An expression cassette comprising the polynucleotide according to any one of embodiments 1 to 48.
Embodiment 50
Liposomes or nanoparticles comprising the polynucleotide according to any one of embodiments 1-48 or the expression cassette according to embodiment 49.
Embodiment 51
A viral vector comprising the polynucleotide according to any one of embodiments 1-48 or the expression cassette according to embodiment 49.
52nd embodiment
50. The embodiment 50, wherein the liposome comprises an internal core comprising the polynucleotide according to any one of embodiments 1-48, which forms a complex with polyethyleneimine (PEI), and an external lipid bilayer. Liposomes or nanoparticles.
Embodiment 53
The liposome or nanoparticle according to any one of embodiments 50-52, wherein the inner core comprises, for example, a liposome-branched polyethyleneimine (PEI) polypeptide (LPP) having a molecular weight of about 10,000 daltons.
Embodiment 54
The external lipid bilayer contains a mixture of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), cholesterol and 1,2-dimyristyl-sn-glycerol, methoxypolyethylene glycol (DMG-PEG2000). The liposome or nanoparticle according to any one of embodiments 50 to 53, which comprises.
Embodiment 55
Transfected or transformed with the polynucleotide according to any one of embodiments 1-48 or the expression cassette according to embodiment 49 or the liposome or nanoparticles according to any one of embodiments 50-54. , Host cell.
Embodiment 56
The host cell according to embodiment 55, wherein the host cell is a prokaryotic cell or a eukaryotic cell.
Embodiment 57
The host cell according to embodiment 55 or 56, wherein the host cell is selected from bacterial cells, mammalian cells, insect cells or plant cells.
Embodiment 58
The polynucleotide according to any one of embodiments 1-48, which is a method of preventing, alleviating, reducing, reversing and / or inhibiting the growth, growth and / or progression of cancer in a required subject. Alternatively, a method comprising administering to said subject the expression cassette according to embodiment 49 or the liposome, nanoparticles or viral vector according to any one of embodiments 50-54.
Embodiment 59
58. The method of embodiment 58, wherein the cancer is selected from the group consisting of breast cancer, lymphoma, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and lung cancer.
Embodiment 60
The polynucleotides are let-7c, miR-298, miR-216, miR-34a, miR-124, miR-328, miR-144, miR-126, miR-16, miR-18, miR-125a, miR. -195, miR-199a, miR-200, miR-224, miR-1291, miR-429, miR-148, miR-144, miR-1, miR-133, miR-888, miR-6775, miR-374 , MiR-92, miR-1180, miR-218, miR-7, miR-378, miR-17, miR-18a, miR-22, miR-122, miR-30b, miR-449, miR-506, miR Embodiment 58 comprising one or more mature miRNAs selected from the group consisting of -98, miR-4458, miR-206, miR-519, miR-93, miR-106, miR-373, and miR-520. Or the method according to 59.
Embodiment 61
58. 60, wherein the cancer is lung cancer and the polynucleotide comprises one or more mature miRNAs selected from the group consisting of miR-34a and miR-124. Method.
Embodiment 62
The cancer is pancreatic cancer and the polynucleotide comprises one or more mature miRNAs selected from the group consisting of miR-1291, miR-34, miR-124, miR-200, and miR-216. , The method according to any one of embodiments 58 to 60.
Embodiment 63
The cancer is hepatocellular carcinoma, and the polynucleotides are let-7c, miR-298, miR-216, miR-124, miR-328, miR-144, miR-126, miR-16, miR-. 18. One of embodiments 58-60, comprising one or more mature miRNAs selected from the group consisting of 18, miR-125a, miR-195, miR-199a, miR-200, and miR-224. the method of.
Embodiment 64
Embodiments 58-63, wherein the polynucleotide, liposome or nanoparticles is administered via a route selected from intravenous, intraarterial, intraperitoneal, intraperitoneal, intrapulmonary, intrahepatic, subcutaneous or intratumoral. The method described in any one of the items.
Embodiment 65
Any of embodiments 58-64, wherein the therapeutic regimen of the polynucleotide, liposome or nanoparticles is administered multiple times, eg, daily, weekly, biweekly, monthly, eg, until a predetermined or desired endpoint is reached. The method described in paragraph 1.
Embodiment 66
The method of any one of embodiments 58-65, wherein the subject exhibits symptoms of cancer, eg, has one or more tumors.
Embodiment 67
The method according to any one of embodiments 58-65, wherein the subject is in remission and is at risk of re-emergence of a tumor.
Embodiment 68
13. The method of any one of embodiments 58-67, further comprising co-administration of one or more chemotherapeutic or anti-cancer agents.
Embodiment 69
28. The method of any one of embodiments 58-68, wherein the subject is tested for overexpression or underexpression of one or more miRNAs prior to administration.
Embodiment 70
One having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs: 85-298. The method according to any one of embodiments 58-69, comprising administering the above hybrid tRNA / premiRNA molecule to said subject.
Embodiment 71
The polynucleotide according to any one of embodiments 1 to 48 or the expression cassette according to embodiment 49, the liposome, nanoparticles or viral vector according to any one of embodiments 50 to 54, and / or embodiments. A kit comprising the host cell according to any one of morphologies 55-57.
The examples and embodiments described herein are for purposes of illustration only, and various modifications or modifications have been proposed to those skilled in the art in light thereof, and are included in the spirit and scope of the present application and the scope of the accompanying claims. It will be understood that it should be. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for any purpose.
Claims (15)
ａ）前記プレｍｉＲＮＡの５’末端、
ｂ）前記プレｍｉＲＮＡの３’末端、
ｃ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の５’、または
ｄ）前記プレｍｉＲＮＡのダイサーもしくはＲＮａｓｅ切断部位の３’
に挿入される、近接する、または作動可能に連結される、請求項１または２に記載のポリヌクレオチド。 The inserted RNA molecule
a) The 5'end of the premiRNA,
b) The 3'end of the premiRNA,
c) 5'of the premiRNA dicer or RNase cleavage site, or d) 3'of the premiRNA dicer or RNase cleavage site.
The polynucleotide according to claim 1 or 2, which is inserted into, adjacent to, or operably linked to.
前記２つ以上のプレｍｉＲＮＡが、同じプレｍｉＲＮＡ分子に由来し、任意で
前記同じプレｍｉＲＮＡ分子に由来する前記２つ以上のプレｍｉＲＮＡが、ヒトプレｍｉＲ－３４ａ分子に由来する、
請求項１～４のいずれか一項に記載のポリヌクレオチド。 The two or more premiRNAs are premiR-34a, premiR-124, premiR-1291, premiR-200b, premiR-200a, premiR-141, premiR-429, premiR-133a, pre. let-7c, pre miR-125a, pre miR-328, pre miR-126, pre miR-298, pre miR-148, pre miR-144, pre miR-1, pre miR-133, pre miR-888, pre miR-6775, pre miR-374, pre miR-92, pre miR-1180, pre miR-218, pre miR-7, pre miR-378, pre miR-17, pre miR-18a, pre miR-22, pre miR-122, pre miR-30b, pre miR-449, pre miR-506, pre miR-98, pre miR-4458, pre miR-206, pre miR-519, pre miR-93, pre miR-106, pre Selected from the group consisting of miR-373, and premiR-520 , optionally
The two or more premiRNAs are derived from the same premiRNA molecule and are optionally
The two or more premiRNAs derived from the same premiRNA molecule are derived from the human premiR-34a molecule.
The polynucleotide according to any one of claims 1 to 4 .
前記がんが、乳がん、リンパ腫、結腸直腸がん、肝細胞がん、膵臓がん、前立腺がん、および肺がんからなる群から選択される、
方法。 A method of preventing, alleviating, reducing, reversing and / or inhibiting the growth, growth and / or progression of cancer in a subject in need thereof, wherein the polynucleotide according to claim 1 is administered to the subject. Including that, optionally,
The cancer is selected from the group consisting of breast cancer, lymphoma, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and lung cancer.
Method.
The polynucleotides are let-7c, miR-298, miR-216, miR-34a, miR-124, miR-328, miR-144, miR-126, miR-16, miR-18, miR-125a, miR. -195, miR-199a, miR-200, miR-224, miR-1291, miR-429, miR-148, miR-144, miR-1, miR-133, miR-888, miR-6775, miR-374 , MiR-92, miR-1180, miR-218, miR-7, miR-378, miR-17, miR-18a, miR-22, miR-122, miR-30b, miR-449, miR-506, miR 14. Claim 14 comprising one or more mature miRNAs selected from the group consisting of -98, miR-4458, miR-206, miR-519, miR-93, miR-106, miR-373, and miR-520. The method described in.
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| PCT/US2019/033232 WO2019226603A1 (en) | 2018-05-22 | 2019-05-21 | Trna/pre-mirna compositions and use in treating cancer |
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| GB201919021D0 (en) | 2019-12-20 | 2020-02-05 | Reneuron Ltd | Nucleic acid constructs for delivering polynucleotides into exosomes |
| CN110946872B (en) * | 2019-12-30 | 2022-11-04 | 北京大学深圳医院 | Application of miR-4491 in preparation of medicine for treating breast cancer |
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