JPWO2020132521A5 - - Google Patents
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- JPWO2020132521A5 JPWO2020132521A5 JP2021535662A JP2021535662A JPWO2020132521A5 JP WO2020132521 A5 JPWO2020132521 A5 JP WO2020132521A5 JP 2021535662 A JP2021535662 A JP 2021535662A JP 2021535662 A JP2021535662 A JP 2021535662A JP WO2020132521 A5 JPWO2020132521 A5 JP WO2020132521A5
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Description
本発明は、その具体的な実施形態と関連して記載されているが、本発明はさらなる修正が可能であり、この出願は、一般に本発明の原理に従い、既知または慣行に含まれ、本発明が関係する技術の範囲内であり、前述の本質的な特徴に適用することができ、特許請求される範囲に従う本開示からのそのような逸脱を含む、本発明のあらゆる変形、使用、または適応を範囲に含むことを意図していることを理解されたい。
本発明は、例えば、以下の項目を提供する。
(項目１)
配列番号３５２６に対して少なくとも９０％同一である配列を含む転写産物の少なくとも１０個の連続する核酸塩基に少なくとも９０％相補的な核酸塩基配列、または配列番号３５２６の連続する１５から５０個の核酸塩基部分を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチドを含む、化合物。
(項目２)
配列番号３５２６に対して少なくとも９０％同一である配列を含む転写産物の少なくとも１０個の連続する核酸塩基に少なくとも９０％相補的な核酸塩基配列、または配列番号３５２６の連続する１５から５０個の核酸塩基部分を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチド。
(項目３)
前記オリゴヌクレオチドが、配列番号１～３５２５のうちのいずれか１つの等しい長さの部分と９０％の同一性を共有する少なくとも連続する１０個の核酸塩基配列を含む、項目１に記載のオリゴヌクレオチドを含む化合物または項目２に記載のオリゴヌクレオチド。
(項目４)
前記オリゴヌクレオチドが、配列番号１～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも連続する１１、１２、１３、１４、１５、１６、または１７個の核酸塩基配列を含む、項目１もしくは３に記載のオリゴヌクレオチドを含む化合物、または項目２もしくは３に記載のオリゴヌクレオチド。
(項目５)
前記オリゴヌクレオチドが、配列番号１～１１６のうちのいずれか１つの等しい長さの部分と９０％の同一性を共有する少なくとも連続する１０個の核酸塩基配列を含む、項目１もしくは３に記載のオリゴヌクレオチドを含む化合物、または項目２もしくは３に記載のオリゴヌクレオチド。
(項目６)
前記オリゴヌクレオチドが、１、４、５、６、８、１０、１２、１３、１５、１７、２８、２９、６２、６２５～６４９、１０４６、１０７１、１１９５～１２２４、１３８８、１４９６～１５６７、２５９１～２６３１、または３３９５～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも連続する１０個の核酸塩基配列を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチドである、項目１もしくは３に記載のオリゴヌクレオチドを含む化合物、または項目２もしくは３に記載のオリゴヌクレオチド。
(項目７)
前記オリゴヌクレオチドが、配列番号４、１０４６、１０７１、１３８８、１５５１、１５４６、または２５９５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも連続する１０個の核酸塩基配列を含む、項目１もしくは３～６のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～６の
いずれか１項に記載のオリゴヌクレオチド。
(項目８)
前記オリゴヌクレオチドが、配列番号１、４、５、６、８、１０、１２、１３、１５、１７、２８、２９、６２、６２５～６４９、１０４６、１０７１、１１９５～１２２４、１３８８、１４９６～１５６７、２５９１～２６３１、または３３９５～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも連続する１１、１２、１３、１４、１５、１６、または１７個の核酸塩基配列を含む、項目１もしくは３～７のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～７のいずれか１項に記載のオリゴヌクレオチド。
(項目９)
前記オリゴヌクレオチドが、配列番号４、１０４６、１０７１、１３８８、１５５１、１５４６、または２５９５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも連続する１１、１２、１３、１４、１５、１６、または１７個の核酸塩基配列を含む、項目１もしくは３～８のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～８のいずれか１項に記載のオリゴヌクレオチド。
(項目１０)
配列番号１、４、５、６、８、１０、１２、１３、１５、１７、２８、２９、６２、６２５～６４９、１０４６、１０７１、１１９５～１２２４、１３８８、１４９６～１５６７、２５９１～２６３１、または３３９５～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも９０％の同一性を共有する少なくとも１０個の連続する核酸塩基配列を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチドを含む化合物。
(項目１１)
前記オリゴヌクレオチドが、配列番号１、４、５、６、８、１０、１２、１３、１５、１７、２８、２９、６２、６２５～６４９、１０４６、１０７１、１１９５～１２２４、１４９６～１５６７、２５９１～２６３１、または３３９５～３５２５のうちのいずれか１つの等しい長さの部分と９０％の同一性を共有する少なくとも１０個の連続する核酸塩基配列を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチド。
(項目１２)
前記オリゴヌクレオチドが、配列番号４、１０４６、１０７１、１３８８、１５５１、１５４６、または２５９５のうちのいずれか１つの等しい長さの部分と９０％の同一性を共有する少なくとも１０個の連続する核酸塩基を含む、項目１０に記載のオリゴヌクレオチドを含む化合物または項目１１に記載のオリゴヌクレオチド。
(項目１３)
前記オリゴヌクレオチドが、配列番号１、４、５、６、８、１０、１２、１３、１５、１７、２８、２９、６２、６２５～６４９、１０４６、１０７１、１１９５～１２２４、１３３８、１４９６～１５６７、２５９１～２６３１、または３３９５～３５２５のうちのいずれか１つの少なくとも１１、１２、１３、１４、１５、１６、１７、１８、または１９個の連続する核酸塩基を含む、項目１０に記載のオリゴヌクレオチドを含む化合物または項目１１に記載のオリゴヌクレオチド。
(項目１４)
前記オリゴヌクレオチドが、配列番号４、１０４６、１０７１、１３８８、１５５１、１５４６、または２５９５のうちのいずれか１つの少なくとも１１、１２、１３、１４、１５、１６、１７、１８，または１９個の連続する核酸塩基を含む、項目１３に記載のオリゴヌクレオチドを含む化合物または項目１３に記載のオリゴヌクレオチド。
(項目１５)
配列番号３５２６の位置３７４、６６１、６５５～６８０、７６５、８３７、１３４７、１３４０～１３７０、１６２９、１７６０、１７５２、１７９５、１７７５、１７４０～１８１５、２８７９、３００８、３１６８、または３１１０～３１７１のうちのいずれか１つの１０個の核酸塩基の範囲内の等しい長さの部分に対して少なくとも９０％相補的である少なくとも１０個の連続する核酸塩基を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチドを含む化合物。
(項目１６)
配列番号３５２６の位置３７４、６６１、６５５～６８０、７６５、８３７、１３４７、１３４０～１３７０、１６２９、１７６０、１７５２、１７９５、１７７５、１７４０～１８１５、２８７９、３００８、３１６８、または３１１０～３１７１のうちの１０個の核酸塩基の範囲内の等しい長さの部分に対して少なくとも９０％相補的である少なくとも１０個の連続する核酸塩基を含み、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチド。
(項目１７)
前記オリゴヌクレオチドが、配列番号３５２６の位置６５５～６８０、１３４０～１３７、１７４０～１８１５、または３１１０～３１７５のいずれか１つ内の核酸塩基の等しい長さ部分に相補的である少なくとも１０個の連続する核酸塩基を含む、項目１５に記載のオリゴヌクレオチドを含む化合物または項目１６に記載のオリゴヌクレオチド。
(項目１８)
前記オリゴヌクレオチドが、配列番号３５２６の位置６５５～６６５、６６０～６７０、６６５～６７５、または６７０～６８０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、項目１７に記載のオリゴヌクレオチドを含む化合物または項目１７に記載のオリゴヌクレオチド。
(項目１９)
前記オリゴヌクレオチドが、配列番号３５２６の位置１３４０～１３５０、１３４５～１３５５、１３５０～１３６０、１３５５～１３６５、または１３６０～１３７０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、項目１７に記載のオリゴヌクレオチドを含む化合物または項目１７に記載のオリゴヌクレオチド。
(項目２０)
前記オリゴヌクレオチドが、配列番号３５２６の位置１７４０～１７５０、１７４５～１７５５、１７５０～１７６０、１７５５～１７６５、１７６０～１７７０、１７６５～１７７５、１７７０～１７８０、１７７５～１７８５、１７８０～１７９０、１７８５～１７９５、１７９０～１８００、１７９５～１８０５、１８００～１８１０、または１８０５～１８１５のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、項目１７に記載のオリゴヌクレオチドを含む化合物または項目１７に記載のオリゴヌクレオチド。
(項目２１)
前記オリゴヌクレオチドが、配列番号３５２６の位置３１１０～３１２０、３１１５～３１２５、３１２０～３１３０、３１２５～３１３５、３１３０～３１４０、３１３５～３１４５、３１４０～３１５０、３１４５～３１５５、３１５０～３１６０、３１５５～３１６５、３１６０～３１７０、３１６５～３１７５、３１７０～３１８０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、項目１７に記載のオリゴヌクレオチドを含む化合物または項目１７に記載のオリゴヌクレオチド。
(項目２２)
前記オリゴヌクレオチドが、配列番号３５２６の位置３７４、６６１、７６５、８３７、１３４７、１６２９、２８７９、３００８、３１６８、１７６０、１７５２、１７９５、１７７５、６５５～６８０、１３４０～１３７０、１７４０～１８１５、または３１１０～３１７１のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１１、１２、１３、１４、１５、１６、１７、１８、または１９個の連続する核酸塩基を含む、項目１５に記載のオリゴヌクレオチドを含む化合物または項目１６に記載のオリゴヌクレオチド。
(項目２３)
前記オリゴヌクレオチドが、配列番号３５２６の位置６５５～６８０、１３４０～１３７、１７４０～１８１５、または３１１０～３１７５のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１１、１２、１３、１４、１５、１６、１７、１８、または１９個の連続する核酸塩基を含む、項目１５に記載のオリゴヌクレオチドを含む化合物または項目１６に記載のオリゴヌクレオチド。
(項目２４)
前記オリゴヌクレオチドが１２～４０個の核酸塩基の長さである、項目１もしくは３～２３のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２３のいずれか１項に記載のいずれかのオリゴヌクレオチド。
(項目２５)
前記オリゴヌクレオチドが、
ａ．連結したデオキシリボヌクレオシド、２’－フルオロアラビノ核酸（ＦＡＮＡ）、及びフルオロシクロヘキセン核酸（Ｆ－ＣｅＮＡ）のうちの１つ以上を含むギャップセグメント、
ｂ．連結したヌクレオシドを含む５’ウィングセグメント、
ｃ．連結したヌクレオシドを含む３’ウィングセグメントを含み、
ｄ．前記ギャップセグメントが、前記５’ウィングセグメントと前記３’ウィングセグメントとの間に配置された配列番号１～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも８０％の同一性を有する少なくとも８つの連続する核酸塩基の領域を含み、前記５’ウィングセグメント及び前記３’ウィングセグメントがそれぞれ、少なくとも２つの連結したヌクレオシドを含み、各々のウィングセグメントの少なくとも１つのヌクレオシドが、修飾糖を含む、項目１、１０、または１５のいずれか１項に記載の化合物。
(項目２６)
ａ．連結したデオキシリボヌクレオシド、２’－フルオロアラビノ核酸（ＦＡＮＡ）、及びフルオロシクロヘキセン核酸（Ｆ－ＣｅＮＡ）のうちの１つ以上を含むギャップセグメント；
ｂ．連結したヌクレオシドを含む５’ウィングセグメント；
ｃ．連結したヌクレオシドを含む３’ウィングセグメントを含み、
ｄ．前記ギャップセグメントが、配列番号１～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも８０％の同一性を有する少なくとも８つの連続する核酸塩基の領域を含み、前記５’ウィングセグメント及び前記３’ウィングセグメントがそれぞれ、少なくとも２つの連結したヌクレオシドを含み、各々のウィングセグメントの少なくとも１つのヌクレオシドが、修飾糖を含む、項目２、１１、または１６のいずれか１項に記載のオリゴヌクレオチド。
(項目２７)
前記オリゴヌクレオチドが、少なくとも１３、１４、１５、１６、１７、１８、１９、または２０個の連結したヌクレオシドを含む、項目２５に記載のオリゴヌクレオチドを含む化合物、または項目２６に記載のオリゴヌクレオチド。
(項目２８)
前記核酸塩基配列の少なくとも１つのヌクレオシド結合が、ホスホジエステル結合、ホスホロチオエート結合、２’－アルコキシ結合、アルキルリン酸エステル結合、アルキルホスホネート結合、ホスホロジチオエート結合、ホスホトリエステル結合、アルキルホスホネート結合、メチルホスホネート結合、ジメチルホスホネート結合、アミノアルキルホスホトリエステル結合、アルキレンホスホネート結合、ホスフィネート結合、ホスホルアミデート結合、ホスホロジアミデート結合、アミノアルキルホスホルアミデート結合、チオホスホルアミデート結合、チオノアルキルホスホネート結合、チオノアルキルホスホトリエステル結合、チオホスフェート結合、セレノホスフェート結合、及びボラノホスフェート結合からなる群から選択される、項目１、もしくは３～２７のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～１７のいずれか１項に記載のオリゴヌクレオチド。
(項目２９)
前記５’ウィングセグメントの少なくとも２つの連結したヌクレオシドが、ホスホジエステルヌクレオシド間結合を介して連結され、前記３’ウィングセグメントの少なくとも２つの連結したヌクレオシドが、ホスホジエステルヌクレオシド間結合を介して連結され、前記ギャップセグメントのヌクレオシド間結合のうちの少なくとも１つが、修飾ヌクレオシド間結合である、項目２５もしくは２７に記載のオリゴヌクレオチドを含む化合物、または項目２６もしくは２７に記載のオリゴヌクレオチド。
(項目３０)
前記核酸塩基配列の少なくとも２つ、３つ、または４つのヌクレオシド間結合がホスホジエステルヌクレオシド間結合である、項目２５もしくは２７～２９のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２９のいずれか１項に記載のオリゴヌクレオチド。
(項目３１)
前記ギャップセグメントのヌクレオシド塩基間の少なくとも１つ、２つ、３つ、または４つヌクレオシド間結合が、ホスホジエステルヌクレオシド間結合である、項目２５もしくは２７～３０のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～３０のいずれか１項に記載のいずれかのオリゴヌクレオチド。
(項目３２)
前記核酸塩基配列の少なくとも２つのヌクレオシド間結合が修飾ヌクレオシド間結合である、項目１、３～２５もしくは２７～３１のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～３１のいずれか１項に記載のオリゴヌクレオチド。
(項目３３)
前記核酸塩基配列の修飾ヌクレオシド間結合が、ホスホロチオエート結合である、項目３２に記載のオリゴヌクレオチドを含む化合物または項目３２に記載のオリゴヌクレオチド。
(項目３４)
前記核酸塩基配列の全てのヌクレオシド間結合がホスホロチオエート結合である、項目３２もしくは３３に記載のオリゴヌクレオチドを含む化合物、または項目３２もしくは３３に記載のオリゴヌクレオチド。
(項目３５)
前記５’ウィングセグメントの少なくとも２つの連結したヌクレオシドが、修飾ヌクレオシド間結合を介して連結されている、項目２５、２７～２８、もしくは３２～３４のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３４のいずれか１項に記載のオリゴヌクレオチド。
(項目３６)
前記３’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、修飾ヌクレオシド間結合を介して連結されている、項目２５、２７～２８、もしくは３２～３４のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３４のいずれか１項に記載のオリゴヌクレオチド。
(項目３７)
前記５’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、ホスホロチオエートヌクレオシド間結合を介して連結され、前記３’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、ホスホロチオエートヌクレオシド間結合を介して連結され、前記ギャップセグメントのヌクレオシド間結合のうちの少なくとも１つが、修飾ヌクレオシド間結合である、項目２５、２７～２８、もしくは３２～３６のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３６のいずれか１項に記載のオリゴヌクレオチド。
(項目３８)
前記核酸塩基配列の少なくとも２つ、３つ、または４つのヌクレオシド間結合がホスホロチオエートヌクレオシド間結合である、項目２５、２７～２８、もしくは３２～３７のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３７のいずれか１項に記載のオリゴヌクレオチド。
(項目３９)
前記ギャップセグメントのヌクレオシド塩基間の少なくとも１つ、２つ、３つ、または４つヌクレオシド間結合が、ホスホロチオエートヌクレオシド間結合である、項目２５、２７～２８、もしくは３２～３８のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３８のいずれか１項に記載のオリゴヌクレオチド。
(項目４０)
前記ホスホロチオエートヌクレオシド間結合がＲｐ配置、ＳＰ配置、またはＲｐとＳｐ配置の任意の組み合わせである、項目２５、２７～２８、もしくは３２～３９のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２６～２８もしくは３２～３９のいずれか１項に記載のオリゴヌクレオチド。
(項目４１)
前記オリゴヌクレオチドが少なくとも１つの修飾核酸塩基を含む、項目１、３～２５もしくは２７～４０のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～４０のいずれか１項に記載のオリゴヌクレオチド。
(項目４２)
前記少なくとも１つの修飾核酸塩基が、５’－メチルシトシン、シュードウリジン、または５－メトキシウリジンである、項目４１に記載のオリゴヌクレオチドを含む化合物、または項目４１に記載のオリゴヌクレオチド。
(項目４３)
前記オリゴヌクレオチドが少なくとも１つの修飾糖部分を含む、項目１、３～２５もしくは２７～４２のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～４２のいずれか１項に記載のオリゴヌクレオチド。
(項目４４)
前記少なくとも１つの修飾糖が二環式糖である、項目４３に記載のオリゴヌクレオチドを含む化合物または項目４３に記載のオリゴヌクレオチド。
(項目４５)
前記二環式糖が、４’－ＣＨ（Ｒ）－Ｏ－２’ブリッジを含み、式中、Ｒが独立して、Ｈ、Ｃ
１
－Ｃ
１２
アルキル、または保護基である、項目４４に記載のオリゴヌクレオチドを含む化合物または項目４４に記載のオリゴヌクレオチド。
(項目４６)
Ｒがメチルである、項目４５に記載のオリゴヌクレオチドを含む化合物または項目４５に記載のオリゴヌクレオチド。
(項目４７)
ＲがＨである、項目４５に記載のオリゴヌクレオチドを含む化合物または項目４５に記載のオリゴヌクレオチド。
(項目４８)
前記修飾糖部分が、２’－ＯＭｅ修飾糖部分、二環式糖部分、２’－Ｏ－メトキシエチル（ＭＯＥ）、２’－デオキシ－２’－フルオロヌクレオシド、２’－フルオロ－β－Ｄ－アラビノヌクレオシド、ロックド核酸（ＬＮＡ）、拘束エチル２’－４’－架橋核酸（ｃＥｔ）、Ｓ－ｃＥｔ、ｔｃＤＮＡ、ヘキシトール核酸（ＨＮＡ）、及び三環類似体（例えば、ｔｃＤＮＡ）のうちの１つである、項目４３に記載のオリゴヌクレオチドを含む化合物または項目４３に記載のオリゴヌクレオチド。
(項目４９)
前記オリゴヌクレオチドがホスホロチオエートヌクレオシド間結合を介して連結している１つ以上の２’－Ｏ－メトキシエチルヌクレオシドを含む、項目１、３～２５、もしくは２７～４８のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～４８のいずれか１項に記載のオリゴヌクレオチド。
(項目５０)
前記オリゴヌクレオチドが、５’末端にホスホロチオエートヌクレオシド間結合を介して連結された３つの連続するヌクレオシド塩基を含み、３’末端にホスホロチオエートヌクレオシド間結合を介して連結された３つの連続するヌクレオシド塩基を含む、項目１、３～２５、もしくは２７～４９のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～４９のいずれか１項に記載のオリゴヌクレオチド。
(項目５１)
前記オリゴヌクレオチドが、ホスホロチオエートヌクレオシド間結合を介して連結された５つの連続するヌクレオシド塩基を含む、項目５０に記載のオリゴヌクレオチドを含む化合物または項目５０に記載のオリゴヌクレオチド。
(項目５２)
前記５つの連続するヌクレオシド塩基のそれぞれが２’－Ｏ－メトキシエチルヌクレオシドである、項目５０もしくは５１に記載のオリゴヌクレオチドを含む化合物、または項目５０もしくは５１に記載のオリゴヌクレオチド。
(項目５３)
前記オリゴヌクレオチドのヌクレオシド塩基のそれぞれが２’－Ｏ－メトキシエチルヌクレオシドである、項目４３～５２のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目４３～５２のいずれか１項に記載のオリゴヌクレオチド。
(項目５４)
前記ギャップセグメントが１つ以上の２’－Ｏ－メトキシエチルヌクレオシドを含む、項目４３～５２のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目４３～５２のいずれか１項に記載のオリゴヌクレオチド。
(項目５５)
前記ギャップセグメントが、ホスホロチオエートヌクレオシド間結合を含み、前記５’ウィングセグメントが、ホスホジエステルヌクレオシド結合を介して連結される２つの連続するヌクレオシド塩基を含み、前記３’ウィングセグメントが、ホスホジエステルヌクレオシド結合を介して連結される２つの連続するヌクレオシド塩基を含む、項目４３～５４のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目４３～５４のいずれか１項に記載のオリゴヌクレオチド。
(項目５６)
前記ギャップセグメントの５つの連続するヌクレオシド塩基が、ホスホロチオエートヌクレオシド間結合を介して連結され、前記５’ウィングセグメントが、少なくとも１つのホスホロチオエートヌクレオシド間結合を含み、前記３’ウィングセグメントが、少なくとも１つのホスホロチオエートヌクレオシド間結合を含む、項目４３～５４のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目４３～５４のいずれか１項に記載のオリゴヌクレオチド。
(項目５７)
１つ以上のキラル中心及び／または二重結合を含む、項目１、３～２５、もしくは２７～５６のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～５７のいずれか１項に記載のオリゴヌクレオチド。
(項目５８)
前記オリゴヌクレオチドが、幾何異性体、エナンチオマー、及びジアステレオマーから選択される立体異性体として存在する、項目５７に記載のオリゴヌクレオチドを含む化合物または項目５７に記載のオリゴヌクレオチド。
(項目５９)
前記オリゴヌクレオチドが、ｅｅｅｅｅ－ｄ１０－ｅｅｅｅｅ、ｄ２０、ｅｅｅｅｅ－ｄ１２－ｅｅｅｅｅ、ｅｅｅｅｅ－ｄ８－ｅｅｅｅｅ、及びｅｅｋｋ－ｄ８－ｋｋｅｅｅのパターンのうちのいずれかの糖修飾を含み、式中、ｅ＝２’－Ｏ－メトキシエチルヌクレオシド；ｄ＝２’－デオキシヌクレオシド；ｋ＝ロックド核酸（ＬＮＡ）、拘束メトキシエチル（ｃＭＯＥ）ヌクレオシド、拘束エチル（ｃＥＴ）ヌクレオシド、またはペプチド核酸（ＰＮＡ）である、項目１、３～２５、もしくは２７のいずれかに記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～２７のいずれかのオリゴヌクレオチド。
(項目６０)
前記オリゴヌクレオチドが、ｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及びｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓのうちのいずれかのヌクレオシド間結合を含み、式中、ｓ＝ホスホロチオエート結合、及びｏ＝ホスホジエステル結合である、項目１、３～２５、２７、もしくは５９のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４、２６、２７、もしくは５９のいずれか１項に記載のオリゴヌクレオチド。
(項目６１)
前記オリゴヌクレオチドが、それぞれ以下のパターンのうちのいずれかの糖修飾とヌクレオシド間結合の組み合わせを含む、項目１、３～２５、２７、５９、もしくは６０のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４、２６、２７、５９、もしくは６０のいずれか１項に記載のオリゴヌクレオチド：
ａ）ｄ２０とｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｂ）ｅｅｅｅｅ－ｄ１０－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｃ）ｅｅｅｅｅ－ｄ１２－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｄ）ｅｅｅｅｅ－ｄ８－ｅｅｅｅｅとｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及び
ｅ）ｅｅｋｋ－ｄ８－ｋｋｅｅｅとｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ。
(項目６２)
前記オリゴヌクレオチドが修飾シトシンを含む、項目１、３～２５、２７、もしくは５９～６１のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４、２６、２７、もしくは５９～６１のいずれか１項に記載のオリゴヌクレオチド。
(項目６３)
前記修飾シトシンが５－メチル－ｄＣである、項目６２に記載のオリゴヌクレオチドを含む化合物または項目６２に記載のオリゴヌクレオチド。
(項目６４)
前記オリゴヌクレオチドが、ｅｅｅｅｅ－ｄ１０－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓの糖修飾及びヌクレオシド間結合の組み合わせを含み、前記シトシンが、５－メチル－ｄＣとして修飾されている、項目６３に記載のオリゴヌクレオチドを含む化合物または項目６３に記載のオリゴヌクレオチド。
(項目６５)
前記オリゴヌクレオチドが、それぞれ以下のパターンのうちのいずれかにおける糖修飾とヌクレオシド間結合の組み合わせを含み、前記オリゴヌクレオチド中のシトシンが未修飾のシトシンである、項目６０もしくは６１に記載のオリゴヌクレオチドを含む化合物、または項目６０もしくは６１に記載のオリゴヌクレオチド：
ａ）ｄ２０とｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｂ）ｅｅｅｅｅ－ｄ１２－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｃ）ｅｅｅｅｅ－ｄ８－ｅｅｅｅｅとｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及び
ｄ）ｅｅｋｋ－ｄ８－ｋｋｅｅｅ及びｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ。
(項目６６)
標的核酸配列の標的領域の核酸塩基配列と相補的であり、前記標的核酸の前記標的領域の核酸塩基配列が、少なくとも１つの非標的核酸配列の核酸塩基配列と１～３個の異なる核酸塩基によって異なり、前記非標的核酸が配列番号３５２６の配列を含む、項目１、３～２５、もしくは２７～５６のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４、もしくは２６～６５のいずれか１項に記載のオリゴヌクレオチドによる、化合物またはオリゴヌクレオチド。
(項目６７)
前記１～３個の異なる核酸塩基が一塩基多型（ＳＮＰ）を含む、項目６６に記載の化合物またはオリゴヌクレオチド。
(項目６８)
前記標的領域に存在するＳＮＰが、配列番号３５２６の等しい長さの部分と比較されるＳＮＰである、項目６７に記載の化合物またはオリゴヌクレオチド。
(項目６９)
前記一塩基多型が、ｒｓ３９７５１５４０３、ｒｓ３９７５１５４０２、ｒｓ５８７７７７２６４、ｒｓ３９７５１５４０４、ｒｓ８６６２４２６３１、ｒｓ８８６０４３４５５、ｒｓ３９７５１５４０７、及びｒｓ３９７５１５４０６からなる群から選択される、項目６６に記載の化合物またはオリゴヌクレオチド。
(項目７０)
前記一塩基多型が、、配列番号３５２６に示される配列の１１１２位のＣからＧ、配列番号３５２６に示される配列の２８４５位のＣからＴ、及び配列番号３５２６に示される配列の８８５位のＧからＴからなる群から選択される、項目６６に記載の化合物またはオリゴヌクレオチド。
(項目７１)
先行項目のいずれか１項に記載の化合物またはオリゴヌクレオチドと、薬学的に許容される担体または賦形剤と、を含む、医薬組成物。
(項目７２)
前記医薬組成物が、局所、髄腔内、嚢内、非経口、経口、肺、気管内、鼻腔内、経皮、直腸、頬側、舌下、膣、または十二指腸内投与に適している、項目７１に記載の医薬組成物。
(項目７３)
先行項目のいずれか１項に記載の化合物またはオリゴヌクレオチドと、脂質ナノ粒子、ポリプレックスナノ粒子、リポプレックスナノ粒子、またはリポソームと、を含む組成物。
(項目７４)
ＫＣＮＴ１関連障害を有する対象の細胞におけるＫＣＮＴ１のレベル及び／または活性を低下させる方法であって、項目１、３～２５、もしくは２７～７０のいずれか１項に記載の化合物、項目２～２４、もしくは２６～７０のいずれか１項に記載のオリゴヌクレオチド、または項目７１もしくは７２に記載の医薬組成物を、細胞におけるＫＣＮＴ１のレベル及び／または活性を下げるのに十分な量及び期間で細胞と接触させることを含む、前記方法。
(項目７５)
前記細胞が中枢神経系の細胞である、項目７４に記載の方法。
(項目７６)
神経疾患を治療することを、それを必要とする対象において行う方法であって、前記患者へ転写産物の阻害剤を投与することを含み、前記転写産物は、配列番号３５２６と少なくとも９０％の同一性を共有する、前記方法。
(項目７７)
前記阻害剤が、項目１、３～２５、もしくは２７～７０のいずれか１項に記載のオリゴヌクレオチドを含む化合物、または項目２～２４もしくは２６～７０のいずれか１項に記載のオリゴヌクレオチド、または項目７１もしくは７２に記載の医薬組成物を含む、項目７６に記載の方法。
(項目７８)
ＫＣＮＴ１関連障害を治療、予防、またはその進行を遅延させることを、それを必要とする対象において行う方法であって、項目１、３～２５、もしくは７０のいずれか１項に記載のオリゴヌクレオチドを含む化合物、項目２～２４もしくは２６～７０のいずれか１項に記載のオリゴヌクレオチド、または項目７１もしくは７２に記載の医薬組成物を、ＫＣＮＴ１関連障害を治療、予防、またはその進行を遅延させるのに十分な量及び期間で前記対象に投与することを含む、前記方法。
(項目７９)
前記ＫＣＮＴ１関連障害が、移動性焦点発作を伴う乳児期てんかん、常染色体優性夜間前頭葉てんかん、ウエスト症候群、点頭てんかん、てんかん性脳症、部分発作、大田原症候群、発達性てんかん性脳症、及びレノックス・ガストー症候群からなる群から選択される、項目７４～７８のいずれか１項に記載の方法。
(項目８０)
前記対象が、ＫＣＮＴ１に機能獲得型変異を有する、項目７４～７９のいずれか１項に記載の方法。
(項目８１)
前記機能獲得型変異が、Ｖ２７１Ｆ、Ｌ２７４Ｉ、Ｇ２８８Ｓ、Ｆ３４６Ｌ、Ｒ３９８Ｑ、Ｒ４２８Ｑ、Ｒ４７４Ｈ、Ｆ５０２Ｖ、Ｍ５１６Ｖ、Ｋ６２９Ｎ、Ｉ７６０Ｍ、Ｙ７９６Ｈ、Ｅ８９３Ｋ、Ｍ８９６Ｉ、Ｍ８９６Ｋ、Ｐ９２４Ｌ、Ｒ９２８Ｃ、Ｆ９３２Ｉ、Ａ９３４Ｔ、Ａ９６６Ｔ、Ｈ２５７Ｄ、Ｒ２６２Ｑ、Ｑ２７０Ｅ、Ｖ３４０Ｍ、Ｃ３７７Ｓ、Ｐ４０９Ｓ、Ｌ４３７Ｆ、Ｒ４７４Ｃ、Ａ４７７Ｔ、Ｒ５６５Ｈ、Ｋ６２９Ｅ、Ｇ６５２Ｖ、Ｉ７６０Ｆ、Ｑ９０６Ｈ、Ｒ９３３Ｇ、Ａ９３４Ｔ、Ｒ９５０Ｑ、Ｒ９６１Ｈ、Ｒ１１０６Ｑ、Ｋ１１５４Ｑ、Ｒ４７４Ｑ、Ｙ１９０３Ｃ、Ｈ４６９Ｌ、Ｍ８９６Ｒ、Ｋ９４６Ｅ、及びＲ９５０Ｌからなる群から選択される、項目８０に記載の方法。
(項目８２)
前記機能獲得型変異が、Ｇ２８８Ｓ、Ｒ３９８Ｑ、Ｒ４２８Ｑ、Ｒ９２８Ｃ、またはＡ９３４Ｔである、項目８０または８１に記載の方法。
(項目８３)
前記方法が、前記ＫＣＮＴ１関連障害の１つ以上の症状を軽減する、項目７４～８２のいずれか１項に記載の方法。
(項目８４)
前記ＫＣＮＴ１関連障害の１つ以上の症状が、長期の発作、頻繁な発作、行動及び発達の遅延、運動及びバランスの問題、整形外科的状態、言語遅延及び発声の問題、成長及び栄養の問題、睡眠困難、慢性感染症、感覚統合障害、自律神経系の乱れ、ならびに発汗からなる群から選択される、項目８３に記載の方法。
(項目８５)
前記オリゴヌクレオチドまたは医薬組成物が、局所的、非経口的、髄腔内、嚢内、経口、直腸、頬側、舌下、膣内、肺内、気管内、鼻腔内、経皮、または十二指腸内に投与される、項目７４～８４のいずれか１項に記載の方法。
(項目８６)
前記患者がヒトである、項目７４～８５のいずれか１項に記載の方法。
(項目８７)
１８～２２個の連結したヌクレオシドの長さであって、Ｈ．ｓａｐｉｅｎｓのＫＣＮＴ１及びＭ．ｍｕｓｃｕｌｕｓのＫＣＮＴ１転写産物の等しい長さの部分に対して少なくとも８５％の配列相補性を有する修飾オリゴヌクレオチドを含む化合物。
(項目８８)
１８～２２個の連結したヌクレオシドの長さであって、Ｈ．ｓａｐｉｅｎｓのＫＣＮＴ１及びＭ．ｆａｓｃｉｃｕｌａｒｉｓのＫＣＮＴ１転写産物の等しい長さの部分に対して少なくとも８５％の配列相補性を有する修飾オリゴヌクレオチドを含む化合物。
(項目８９)
１８～２２個の連結したヌクレオシドの長さであって、Ｈ．ｓａｐｉｅｎｓのＫＣＮＴ１、Ｍ．ｍｕｓｃｕｌｕｓのＫＣＮＴ１、及び／またはＭ．ｆａｓｃｉｃｕｌａｒｉｓのＫＣＮＴ１転写産物の等しい長さの部分に対して少なくとも８５％の配列相補性を有する修飾オリゴヌクレオチドを含む、化合物。
(項目９０)
前記オリゴヌクレオチドが、４０％～７０％のＧＣ含量を含む、項目８７～８９のいずれか１項に記載の化合物。
(項目９１)
前記オリゴヌクレオチドが、Ｈ．ｓａｐｉｅｎｓのＫＣＮＴ１転写産物に対して２つ以下のミスマッチを含む、項目８７～９０のいずれか１項に記載の化合物。
(項目９２)
前記オリゴヌクレオチドが、任意の非ＫＣＮＴ１転写産物に対して少なくとも３つのミスマッチを含む、項目８７～９１のいずれか１項に記載の化合物。
(項目９３)
前記オリゴヌクレオチドがＧＧＧＧの４塩基組を欠いている、項目８７～９２のいずれか１項に記載の化合物。
(項目９４)
前記オリゴヌクレオチドが配列番号３５１２～３５２５のいずれでもない、項目７４～８６のいずれか１項に記載の方法。
(項目９５)
前記オリゴヌクレオチドが配列番号３５１２～３５２５のいずれでもない、項目７１または７２に記載の医薬組成物。
While the invention has been described in connection with specific embodiments thereof, the invention is capable of further modifications, and this application is generally consistent with the principles of the invention, known or practiced, and the invention. Any variation, use, or adaptation of the invention that is within the skill of the art to which it pertains, is applicable to the essential features set forth above, and includes such departures from the present disclosure in accordance with the scope of the claims. It should be understood that the scope is intended to include
The present invention provides, for example, the following items.
(Item 1)
a nucleobase sequence that is at least 90% complementary to at least 10 contiguous nucleobases of a transcript comprising a sequence that is at least 90% identical to SEQ ID NO:3526, or 15 to 50 contiguous nucleic acids of SEQ ID NO:3526 A compound comprising an oligonucleotide comprising a base moiety, wherein at least one nucleoside linkage of said nucleobase sequence is a modified internucleoside linkage.
(Item 2)
a nucleobase sequence that is at least 90% complementary to at least 10 contiguous nucleobases of a transcript comprising a sequence that is at least 90% identical to SEQ ID NO:3526, or 15 to 50 contiguous nucleic acids of SEQ ID NO:3526 An oligonucleotide comprising a base moiety, wherein at least one nucleoside linkage of said nucleobase sequence is a modified internucleoside linkage.
(Item 3)
The oligonucleotide of item 1, wherein said oligonucleotide comprises at least 10 contiguous nucleobase sequences sharing 90% identity with an equal length portion of any one of SEQ ID NOs: 1-3525. or the oligonucleotide of item 2.
(Item 4)
at least 11, 12, 13, 14, 15, 16, or 17 contiguous oligonucleotides that share at least 90% identity with an equal length portion of any one of SEQ ID NOs: 1-3525 A compound comprising the oligonucleotide of items 1 or 3, or the oligonucleotide of items 2 or 3, which comprises the nucleobase sequence of
(Item 5)
4. The method of claim 1 or 3, wherein said oligonucleotide comprises at least 10 contiguous nucleobase sequences sharing 90% identity with an equal length portion of any one of SEQ ID NOS: 1-116. A compound comprising an oligonucleotide or an oligonucleotide according to items 2 or 3.
(Item 6)
the oligonucleotide is ~2631, or at least 10 contiguous nucleobase sequences sharing at least 90% identity with an equal length portion of any one of 3395-3525, wherein at least one nucleoside of said nucleobase sequence A compound comprising the oligonucleotide according to items 1 or 3, or the oligonucleotide according to items 2 or 3, which is an oligonucleotide, wherein the linkage is a modified internucleoside linkage.
(Item 7)
at least 10 contiguous nucleic acids wherein said oligonucleotide shares at least 90% identity with an equal length portion of any one of SEQ ID NOs: 4, 1046, 1071, 1388, 1551, 1546, or 2595 A compound comprising the oligonucleotide according to any one of items 1 or 3 to 6, which comprises a nucleotide sequence, or items 2 to 6
Oligonucleotide according to any one of paragraphs.
(Item 8)
SEQ ID NOs: 1, 4, 5, 6, 8, 10, 12, 13, 15, 17, 28, 29, 62, 625-649, 1046, 1071, 1195-1224, 1388, 1496-1567 , 2591-2631, or 3395-3525, at least 11, 12, 13, 14, 15, 16, or 17 contiguous sequences sharing at least 90% identity with an equal length portion of any one of A compound comprising the oligonucleotide of any one of items 1 or 3-7, or the oligonucleotide of any one of items 2-7, comprising a nucleobase sequence.
(Item 9)
at least contiguous 11, 12, wherein said oligonucleotide shares at least 90% identity with an equal length portion of any one of SEQ ID NOs: 4, 1046, 1071, 1388, 1551, 1546, or 2595; A compound comprising the oligonucleotide of any one of items 1 or 3-8, comprising 13, 14, 15, 16, or 17 nucleobase sequences, or any one of items 2-8. of oligonucleotides.
(Item 10)
SEQ. or at least 10 contiguous nucleobase sequences sharing at least 90% identity with an equal length portion of any one of 3395-3525, wherein at least one nucleoside bond of said nucleobase sequence is modified A compound comprising an oligonucleotide that is an internucleoside linkage.
(Item 11)
SEQ ID NOs: 1, 4, 5, 6, 8, 10, 12, 13, 15, 17, 28, 29, 62, 625-649, 1046, 1071, 1195-1224, 1496-1567, 2591 ~2631, or at least 10 contiguous nucleobase sequences sharing 90% identity with an equal length portion of any one of 3395-3525, wherein at least one nucleoside bond of said nucleobase sequence is a modified internucleoside linkage.
(Item 12)
at least 10 contiguous nucleobases wherein said oligonucleotide shares 90% identity with an equal length portion of any one of SEQ ID NO: 4, 1046, 1071, 1388, 1551, 1546, or 2595 A compound comprising the oligonucleotide of item 10 or the oligonucleotide of item 11, comprising:
(Item 13)
SEQ ID NOs: 1, 4, 5, 6, 8, 10, 12, 13, 15, 17, 28, 29, 62, 625-649, 1046, 1071, 1195-1224, 1338, 1496-1567 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous nucleobases of any one of , 2591-2631, or 3395-3525. 12. A compound comprising a nucleotide or an oligonucleotide according to item 11.
(Item 14)
said oligonucleotide is at least 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous of any one of SEQ ID NOs: 4, 1046, 1071, 1388, 1551, 1546, or 2595; 14. A compound comprising the oligonucleotide of item 13 or the oligonucleotide of item 13, comprising a nucleobase of
(Item 15)
of positions 374, 661, 655-680, 765, 837, 1347, 1340-1370, 1629, 1760, 1752, 1795, 1775, 1740-1815, 2879, 3008, 3168, or 3110-3171 of SEQ ID NO:3526 comprising at least 10 contiguous nucleobases that are at least 90% complementary to a portion of equal length within any one 10 nucleobase sequence, wherein at least one nucleoside bond of said nucleobase sequence comprises A compound comprising an oligonucleotide that is a modified internucleoside linkage.
(Item 16)
of positions 374, 661, 655-680, 765, 837, 1347, 1340-1370, 1629, 1760, 1752, 1795, 1775, 1740-1815, 2879, 3008, 3168, or 3110-3171 of SEQ ID NO:3526 comprising at least 10 contiguous nucleobases that are at least 90% complementary to a portion of equal length within 10 nucleobases, wherein at least one nucleoside linkage of said nucleobase sequence is a modified internucleoside linkage; is an oligonucleotide.
(Item 17)
at least 10 stretches wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-680, 1340-137, 1740-1815, or 3110-3175 of SEQ ID NO:3526 17. A compound comprising the oligonucleotide of item 15 or the oligonucleotide of item 16, comprising a nucleobase of
(Item 18)
at least 10 wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-665, 660-670, 665-675, or 670-680 of SEQ ID NO:3526 18. A compound comprising the oligonucleotide of item 17 or the oligonucleotide of item 17, comprising 10 consecutive nucleobases.
(Item 19)
said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 1340-1350, 1345-1355, 1350-1360, 1355-1365, or 1360-1370 of SEQ ID NO:3526 A compound comprising the oligonucleotide of item 17 or the oligonucleotide of item 17, comprising at least 10 contiguous nucleobases of .
(Item 20)
wherein said oligonucleotide comprises positions 1740-1750, 1745-1755, 1750-1760, 1755-1765, 1760-1770, 1765-1775, 1770-1780, 1775-1785, 1780-1790, 1785-1795 of SEQ ID NO: 3526; An item comprising at least 10 contiguous nucleobases complementary to an equal length portion of nucleobases within any one of 1790-1800, 1795-1805, 1800-1810, or 1805-1815 18. A compound comprising the oligonucleotide of item 17 or the oligonucleotide of item 17.
(Item 21)
wherein the oligonucleotide is at positions 3110-3120, 3115-3125, 3120-3130, 3125-3135, 3130-3140, 3135-3145, 3140-3150, 3145-3155, 3150-3160, 3155-3165 of SEQ ID NO: 3526; 18. The oligo of item 17, comprising at least 10 contiguous nucleobases complementary to an equal length portion of nucleobases within any one of 3160-3170, 3165-3175, 3170-3180. 18. A compound comprising nucleotides or an oligonucleotide according to item 17.
(Item 22)
said oligonucleotide is at position 374, 661, 765, 837, 1347, 1629, 2879, 3008, 3168, 1760, 1752, 1795, 1775, 655-680, 1340-1370, 1740-1815, or 3110 of SEQ ID NO: 3526 at least 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous nucleobases that are complementary to an equal length portion of the nucleobases within any one of -3171 A compound comprising the oligonucleotide of item 15 or the oligonucleotide of item 16, comprising:
(Item 23)
at least 11 wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-680, 1340-137, 1740-1815, or 3110-3175 of SEQ ID NO:3526 16. A compound comprising the oligonucleotide of item 15 or the oligonucleotide of item 16, comprising 12, 13, 14, 15, 16, 17, 18, or 19 contiguous nucleobases.
(Item 24)
A compound comprising the oligonucleotide of any one of items 1 or 3-23, or the compound of any one of items 2-23, wherein said oligonucleotide is 12-40 nucleobases in length. any oligonucleotide.
(Item 25)
The oligonucleotide is
a. gap segments comprising one or more of linked deoxyribonucleosides, 2′-fluoroarabinonucleic acids (FANA), and fluorocyclohexene nucleic acids (F-CeNA);
b. a 5' wing segment comprising linked nucleosides;
c. comprising a 3' wing segment comprising linked nucleosides;
d. at least the gap segment has at least 80% identity with an equal length portion of any one of SEQ ID NOs: 1-3525 located between the 5′ wing segment and the 3′ wing segment; comprising a region of 8 contiguous nucleobases, wherein said 5′ wing segment and said 3′ wing segment each comprise at least two linked nucleosides, wherein at least one nucleoside of each wing segment comprises a modified sugar; 16. The compound of any one of items 1, 10, or 15.
(Item 26)
a. gap segments comprising one or more of linked deoxyribonucleosides, 2′-fluoroarabinonucleic acids (FANA), and fluorocyclohexene nucleic acids (F-CeNA);
b. a 5' wing segment comprising linked nucleosides;
c. comprising a 3' wing segment comprising linked nucleosides;
d. said gap segment comprises a region of at least 8 contiguous nucleobases having at least 80% identity to an equal length portion of any one of SEQ ID NOS: 1-3525, said 5' wing segment and said 17. The oligonucleotide of any one of items 2, 11, or 16, wherein each 3' wing segment comprises at least two linked nucleosides, and at least one nucleoside of each wing segment comprises a modified sugar.
(Item 27)
A compound comprising the oligonucleotide of item 25, or the oligonucleotide of item 26, wherein said oligonucleotide comprises at least 13, 14, 15, 16, 17, 18, 19, or 20 linked nucleosides.
(Item 28)
at least one nucleoside bond of said nucleobase sequence is a phosphodiester bond, a phosphorothioate bond, a 2'-alkoxy bond, an alkyl phosphate bond, an alkyl phosphonate bond, a phosphorodithioate bond, a phosphotriester bond, an alkyl phosphonate bond; methylphosphonate linkage, dimethylphosphonate linkage, aminoalkylphosphotriester linkage, alkylenephosphonate linkage, phosphinate linkage, phosphoramidate linkage, phosphorodiamidate linkage, aminoalkylphosphoramidate linkage, thiophosphoramidate linkage, thio 28. The oligo of any one of items 1 or 3-27, which is selected from the group consisting of noalkylphosphonate linkages, thionoalkylphosphotriester linkages, thiophosphate linkages, selenophosphate linkages, and boranophosphate linkages. A compound comprising a nucleotide, or an oligonucleotide according to any one of items 2-17.
(Item 29)
at least two linked nucleosides of said 5' wing segment are linked via phosphodiester internucleoside linkages and at least two linked nucleosides of said 3' wing segment are linked via phosphodiester internucleoside linkages; A compound comprising the oligonucleotide of items 25 or 27, or the oligonucleotide of items 26 or 27, wherein at least one of the internucleoside linkages of said gap segment is a modified internucleoside linkage.
(Item 30)
A compound comprising the oligonucleotide of any one of items 25 or 27-29, or item 26, wherein at least two, three, or four internucleoside linkages of said nucleobase sequence are phosphodiester internucleoside linkages 30. The oligonucleotide of any one of claims 1-29.
(Item 31)
31. The oligonucleotide of any one of items 25 or 27-30, wherein at least one, two, three or four internucleoside linkages between nucleoside bases of said gap segment are phosphodiester internucleoside linkages. or any oligonucleotide according to any one of items 26-30.
(Item 32)
A compound comprising the oligonucleotide of any one of items 1, 3-25 or 27-31, or items 2-24 or 26, wherein at least two internucleoside linkages of said nucleobase sequence are modified internucleoside linkages. 32. The oligonucleotide of any one of claims 1-31.
(Item 33)
33. A compound comprising the oligonucleotide of item 32 or the oligonucleotide of item 32, wherein the modified internucleoside linkages of said nucleobase sequence are phosphorothioate linkages.
(Item 34)
34. A compound comprising the oligonucleotide of items 32 or 33, or the oligonucleotide of items 32 or 33, wherein all internucleoside linkages of said nucleobase sequence are phosphorothioate linkages.
(Item 35)
A compound comprising the oligonucleotide of any one of items 25, 27-28, or 32-34, wherein at least two linked nucleosides of said 5' wing segment are linked via modified internucleoside linkages. , or the oligonucleotide of any one of items 26-28 or 32-34.
(Item 36)
35. The oligonucleotide of any one of items 25, 27-28, or 32-34, wherein said at least two linked nucleosides of said 3' wing segment are linked via modified internucleoside linkages. A compound or oligonucleotide according to any one of items 26-28 or 32-34.
(Item 37)
said at least two linked nucleosides of said 5' wing segment are linked via phosphorothioate internucleoside linkages and said at least two linked nucleosides of said 3' wing segment are linked via phosphorothioate internucleoside linkages; a compound comprising the oligonucleotide of any one of items 25, 27-28, or 32-36, or items 26-36, wherein at least one of the internucleoside linkages of said gap segment is a modified internucleoside linkage The oligonucleotide according to any one of 28 or 32-36.
(Item 38)
A compound comprising the oligonucleotide of any one of items 25, 27-28, or 32-37, wherein at least two, three, or four internucleoside linkages of said nucleobase sequence are phosphorothioate internucleoside linkages. , or the oligonucleotide of any one of items 26-28 or 32-37.
(Item 39)
39. Any one of items 25, 27-28, or 32-38, wherein at least 1, 2, 3, or 4 internucleoside linkages between nucleoside bases of said gap segment are phosphorothioate internucleoside linkages. A compound comprising an oligonucleotide as described, or an oligonucleotide according to any one of items 26-28 or 32-38.
(Item 40)
a compound comprising the oligonucleotide of any one of items 25, 27-28, or 32-39, wherein said phosphorothioate internucleoside linkages are of the Rp configuration, the SP configuration, or any combination of Rp and Sp configurations; or The oligonucleotide of any one of items 26-28 or 32-39.
(Item 41)
A compound comprising the oligonucleotide of any one of items 1, 3-25 or 27-40, or any one of items 2-24 or 26-40, wherein said oligonucleotide comprises at least one modified nucleobase The oligonucleotide according to paragraph.
(Item 42)
A compound comprising the oligonucleotide of item 41, or the oligonucleotide of item 41, wherein said at least one modified nucleobase is 5'-methylcytosine, pseudouridine, or 5-methoxyuridine.
(Item 43)
A compound comprising the oligonucleotide of any one of items 1, 3-25 or 27-42, or any one of items 2-24 or 26-42, wherein said oligonucleotide comprises at least one modified sugar moiety The oligonucleotide according to paragraph.
(Item 44)
A compound comprising the oligonucleotide of item 43 or the oligonucleotide of item 43, wherein said at least one modified sugar is a bicyclic sugar.
(Item 45)
according to item 44, wherein said bicyclic sugar comprises a 4'-CH(R)-O-2' bridge, wherein R is independently H, C1 - C12 alkyl, or a protecting group 45. A compound comprising an oligonucleotide according to item 44 or an oligonucleotide according to item 44.
(Item 46)
A compound comprising the oligonucleotide of item 45 or the oligonucleotide of item 45, wherein R is methyl.
(Item 47)
A compound comprising the oligonucleotide of item 45 or the oligonucleotide of item 45, wherein R is H.
(Item 48)
said modified sugar moieties are 2'-OMe modified sugar moieties, bicyclic sugar moieties, 2'-O-methoxyethyl (MOE), 2'-deoxy-2'-fluoronucleosides, 2'-fluoro-β-D - of arabinonucleosides, locked nucleic acids (LNA), constrained ethyl 2'-4'-bridged nucleic acids (cEt), S-cEt, tcDNA, hexitol nucleic acids (HNA), and tricyclic analogues (e.g., tcDNA) A compound comprising an oligonucleotide according to item 43 or an oligonucleotide according to item 43 which is one.
(Item 49)
49. The oligo of any one of items 1, 3-25, or 27-48, wherein said oligonucleotide comprises one or more 2'-O-methoxyethyl nucleosides linked via phosphorothioate internucleoside linkages. A compound comprising a nucleotide, or an oligonucleotide according to any one of items 2-24 or 26-48.
(Item 50)
The oligonucleotide comprises three consecutive nucleoside bases linked via phosphorothioate internucleoside linkages at the 5' end and three consecutive nucleoside bases linked via phosphorothioate internucleoside linkages at the 3' end. , a compound comprising the oligonucleotide of any one of items 1, 3-25, or 27-49, or the oligonucleotide of any one of items 2-24 or 26-49.
(Item 51)
51. A compound comprising the oligonucleotide of item 50 or the oligonucleotide of item 50, wherein said oligonucleotide comprises five consecutive nucleoside bases linked via phosphorothioate internucleoside linkages.
(Item 52)
52. A compound comprising the oligonucleotide of items 50 or 51, or the oligonucleotide of items 50 or 51, wherein each of said five consecutive nucleoside bases is a 2'-O-methoxyethyl nucleoside.
(Item 53)
A compound comprising the oligonucleotide of any one of items 43-52, or any one of items 43-52, wherein each of the nucleoside bases of said oligonucleotide is a 2'-O-methoxyethyl nucleoside. of oligonucleotides.
(Item 54)
A compound comprising the oligonucleotide of any one of items 43-52, wherein said gap segment comprises one or more 2'-O-methoxyethyl nucleosides, or any one of items 43-52. oligonucleotide.
(Item 55)
the gap segment comprises phosphorothioate internucleoside linkages, the 5' wing segment comprises two consecutive nucleoside bases linked via phosphodiester nucleoside linkages, and the 3' wing segment comprises phosphodiester nucleoside linkages. A compound comprising the oligonucleotide of any one of items 43-54, or the oligonucleotide of any one of items 43-54, comprising two consecutive nucleoside bases linked via.
(Item 56)
five consecutive nucleoside bases of said gap segment are linked via phosphorothioate internucleoside linkages, said 5' wing segment comprises at least one phosphorothioate internucleoside linkage, and said 3' wing segment comprises at least one phosphorothioate A compound comprising the oligonucleotide of any one of items 43-54, or the oligonucleotide of any one of items 43-54, comprising an internucleoside linkage.
(Item 57)
A compound comprising the oligonucleotide of any one of items 1, 3-25, or 27-56, containing one or more chiral centers and/or double bonds, or of items 2-24 or 26-57 Oligonucleotide according to any one of paragraphs.
(Item 58)
A compound comprising the oligonucleotide of item 57 or the oligonucleotide of item 57, wherein said oligonucleotide exists as stereoisomers selected from geometric isomers, enantiomers and diastereomers.
(Item 59)
wherein the oligonucleotide comprises sugar modifications in any of the following patterns: eeeee-d10-eeeeee, d20, eeeee-d12-eeeeee, eeeee-d8-eeeee, and eekk-d8-kkeee, wherein e=2 d = 2'-deoxynucleoside; k = locked nucleic acid (LNA), constrained methoxyethyl (cMOE) nucleoside, constrained ethyl (cET) nucleoside, or peptide nucleic acid (PNA), item 1 , 3-25, or 27, or the oligonucleotide of any of items 2-24 or 26-27.
(Item 60)
wherein said oligonucleotide comprises an internucleoside linkage of any of ssssssssssssssssss, ssssssssssssssssssss, sooossssssssssss, and soossssssssssooss, wherein s = phosphorothioate linkage and o = phosphodiester linkage, items 1, 73-25, 25, , or a compound comprising the oligonucleotide of any one of items 2-24, 26, 27, or 59, or the oligonucleotide of any one of items 2-24, 26, 27, or 59.
(Item 61)
The oligonucleotide of any one of items 1, 3-25, 27, 59, or 60, wherein said oligonucleotide comprises a combination of sugar modifications and internucleoside linkages of any of the following patterns, respectively: A compound comprising, or the oligonucleotide of any one of items 2-24, 26, 27, 59, or 60:
a) d20 and ssssssssssssssssssss,
b) eeeee-d10-eeeee and sssssssssssssssssss,
c) eeeee-d12-eeeee and sssssssssssssssssss, d) eeeee-d8-eeeee and sooosssssssssooss, and
e) eekk-d8-kkeee and soosssssssssooss.
(Item 62)
A compound comprising the oligonucleotide of any one of items 1, 3-25, 27, or 59-61, or items 2-24, 26, 27, or 59-61, wherein said oligonucleotide comprises a modified cytosine Oligonucleotide according to any one of.
(Item 63)
A compound comprising the oligonucleotide of item 62 or the oligonucleotide of item 62, wherein said modified cytosine is 5-methyl-dC.
(Item 64)
or 64. The oligonucleotide of item 63.
(Item 65)
62. The oligonucleotide of item 60 or 61, wherein said oligonucleotide comprises a combination of sugar modifications and internucleoside linkages in any of the following patterns, respectively, and wherein the cytosines in said oligonucleotide are unmodified cytosines: A compound comprising, or an oligonucleotide according to items 60 or 61:
a) d20 and ssssssssssssssssssss,
b) eeeee-d12-eeeee and sssssssssssssssssss, c) eeeee-d8-eeeee and sooosssssssssooss, and
d) eekk-d8-kkeee and soosssssssssooss.
(Item 66)
complementary to the nucleobase sequence of a target region of a target nucleic acid sequence, wherein the nucleobase sequence of said target region of said target nucleic acid is separated from the nucleobase sequence of at least one non-target nucleic acid sequence by 1-3 different nucleobases; A compound comprising the oligonucleotide of any one of items 1, 3-25, or 27-56, or items 2-24, or 26-65, wherein, differently, said non-target nucleic acid comprises the sequence of SEQ ID NO: 3526 A compound or oligonucleotide according to any one of Claims 1 to 3.
(Item 67)
67. The compound or oligonucleotide of item 66, wherein said 1-3 different nucleobases comprise single nucleotide polymorphisms (SNPs).
(Item 68)
68. The compound or oligonucleotide of item 67, wherein the SNP present in the target region is a SNP that is compared to an equal length portion of SEQ ID NO:3526.
(Item 69)
67. The compound or oligonucleotide of item 66, wherein the single nucleotide polymorphism is selected from the group consisting of rs397515403, rs397515402, rs587777264, rs397515404, rs866242631, rs886043455, rs397515407, and rs397515406.
(Item 70)
The single nucleotide polymorphism is C to G at position 1112 in the sequence shown in SEQ ID NO: 3526, C to T at position 2845 in the sequence shown in SEQ ID NO: 3526, and position 885 in the sequence shown in SEQ ID NO: 3526 67. The compound or oligonucleotide of item 66, selected from the group consisting of G to T.
(Item 71)
A pharmaceutical composition comprising a compound or oligonucleotide according to any one of the preceding items and a pharmaceutically acceptable carrier or excipient.
(Item 72)
wherein said pharmaceutical composition is suitable for topical, intrathecal, intravesical, parenteral, oral, pulmonary, intratracheal, intranasal, transdermal, rectal, buccal, sublingual, vaginal, or intraduodenal administration. 71. The pharmaceutical composition according to 71.
(Item 73)
A composition comprising a compound or oligonucleotide according to any one of the preceding items and lipid nanoparticles, polyplex nanoparticles, lipoplex nanoparticles or liposomes.
(Item 74)
A method of reducing the level and/or activity of KCNT1 in cells of a subject with a KCNT1-associated disorder, comprising: the compound of any one of items 1, 3-25, or 27-70, items 2-24, Alternatively, the oligonucleotide according to any one of items 26 to 70, or the pharmaceutical composition according to items 71 or 72, is contacted with cells in an amount and for a period of time sufficient to reduce the level and/or activity of KCNT1 in cells. The method as described above, comprising causing
(Item 75)
75. The method of item 74, wherein said cells are cells of the central nervous system.
(Item 76)
A method of treating a neurological disorder in a subject in need thereof, comprising administering to said patient an inhibitor of a transcript, wherein said transcript is at least 90% identical to SEQ ID NO: 3526 sharing sex.
(Item 77)
a compound wherein said inhibitor comprises the oligonucleotide of any one of items 1, 3-25, or 27-70, or the oligonucleotide of any one of items 2-24 or 26-70; Or the method of item 76, comprising the pharmaceutical composition of item 71 or 72.
(Item 78)
A method of treating, preventing, or delaying progression of a KCNT1-associated disorder in a subject in need thereof, comprising the oligonucleotide of any one of items 1, 3-25, or 70. A compound comprising, the oligonucleotide of any one of items 2-24 or 26-70, or the pharmaceutical composition of items 71 or 72, is used to treat, prevent, or delay the progression of a KCNT1-associated disorder. administering to the subject in an amount and for a period of time sufficient to
(Item 79)
The KCNT1-related disorder is infantile epilepsy with migratory focal seizures, autosomal dominant nocturnal frontal lobe epilepsy, West syndrome, spallation epilepsy, epileptic encephalopathy, partial seizures, Otawara syndrome, developmental epileptic encephalopathy, and Lennox-Gastaut 79. The method of any one of items 74-78, selected from the group consisting of syndromes.
(Item 80)
80. The method of any one of items 74-79, wherein the subject has a gain-of-function mutation in KCNT1.
(Item 81)
The gain-of-function mutation is V271F, L274I, G288S, F346L, R398Q, R428Q, R474H, F502V, M516V, K629N, I760M, Y796H, E893K, M896I, M896K, P924L, R928C, F932I, A934T, H257T, A966T 、Ｑ２７０Ｅ、Ｖ３４０Ｍ、Ｃ３７７Ｓ、Ｐ４０９Ｓ、Ｌ４３７Ｆ、Ｒ４７４Ｃ、Ａ４７７Ｔ、Ｒ５６５Ｈ、Ｋ６２９Ｅ、Ｇ６５２Ｖ、Ｉ７６０Ｆ、Ｑ９０６Ｈ、Ｒ９３３Ｇ、Ａ９３４Ｔ、Ｒ９５０Ｑ、Ｒ９６１Ｈ、Ｒ１１０６Ｑ、Ｋ１１５４Ｑ、Ｒ４７４Ｑ、Ｙ１９０３Ｃ、Ｈ４６９Ｌ、Ｍ８９６Ｒ、Ｋ９４６Ｅ、及びＲ９５０Ｌから81. The method of item 80, selected from the group consisting of:
(Item 82)
82. The method of item 80 or 81, wherein said gain-of-function mutation is G288S, R398Q, R428Q, R928C, or A934T.
(Item 83)
83. The method of any one of items 74-82, wherein said method alleviates one or more symptoms of said KCNT1-associated disorder.
(Item 84)
one or more symptoms of said KCNT1-related disorder are prolonged seizures, frequent seizures, behavioral and developmental delays, movement and balance problems, orthopedic conditions, language delay and vocalization problems, growth and nutrition problems, 84. The method of item 83, selected from the group consisting of difficulty sleeping, chronic infections, impaired sensory integration, disturbances of the autonomic nervous system, and sweating.
(Item 85)
wherein said oligonucleotide or pharmaceutical composition is topically, parenterally, intrathecally, intracapsular, oral, rectal, buccal, sublingual, intravaginal, intrapulmonary, intratracheal, intranasal, transdermal, or intraduodenal 85. The method of any one of items 74-84, wherein the method is administered to
(Item 86)
86. The method of any one of items 74-85, wherein said patient is a human.
(Item 87)
18-22 linked nucleosides in length, and the H. sapiens KCNT1 and M. A compound comprising a modified oligonucleotide having at least 85% sequence complementarity to an equal length portion of the KCNT1 transcript of musculus.
(Item 88)
18-22 linked nucleosides in length, and the H. sapiens KCNT1 and M. A compound comprising a modified oligonucleotide having at least 85% sequence complementarity to an equal length portion of the KCNT1 transcript of Fascicularis.
(Item 89)
18-22 linked nucleosides in length, and the H. sapiens KCNT1, M. musculus KCNT1 and/or M. musculus. A compound comprising a modified oligonucleotide having at least 85% sequence complementarity to an equal length portion of the KCNT1 transcript of Fascicularis.
(Item 90)
89. The compound of any one of items 87-89, wherein said oligonucleotide comprises a GC content of 40%-70%.
(Item 91)
Said oligonucleotide is H. 91. The compound of any one of items 87-90, comprising no more than two mismatches to the KCNT1 transcript of sapiens.
(Item 92)
92. The compound of any one of items 87-91, wherein said oligonucleotide contains at least 3 mismatches to any non-KCNT1 transcript.
(Item 93)
93. The compound of any one of items 87-92, wherein said oligonucleotide lacks the GGGG tetrad.
(Item 94)
87. The method of any one of items 74-86, wherein said oligonucleotide is none of SEQ ID NOS:3512-3525.
(Item 95)
73. The pharmaceutical composition of items 71 or 72, wherein said oligonucleotide is not any of SEQ ID NOS:3512-3525.
Claims (46)
前記オリゴヌクレオチドが、配列番号３５２６の位置３７４、６５５～６８０、７６５、８３７、１３４０～１３７０、１６２９、１７４０～１８１５、２８７９、３００８、または３１１０～３１７５のうちのいずれか１つの１０個の核酸塩基の範囲内の等しい長さの部分に対して少なくとも９０％相補的である少なくとも１０個の連続する核酸塩基を含む、あるいは
前記オリゴヌクレオチドが、配列番号３５２６の位置３７４、６６１、７６５、８３７、１１４９、１１５０、１１７６、１３４７、１５９８、１６２９、１７６０、１７５２、１７９５、１７７５、１７９３、１７９９、２８７９、３００８、３１１４、または３１６８のうちのいずれか１つの１０個の核酸塩基の範囲内の等しい長さの部分に対して少なくとも９０％相補的である少なくとも１０個の連続する核酸塩基を含み；かつ、前記核酸塩基配列の少なくとも１つのヌクレオシド結合が修飾ヌクレオシド間結合である、オリゴヌクレオチドまたは化合物。 An oligonucleotide or a compound comprising said oligonucleotide,
wherein said oligonucleotide comprises any one of positions 374 , 655-680 , 765, 837, 1340-1370 , 1629, 1740-1815, 2879, 3008 , or 3110-3175 of SEQ ID NO:3526; contains at least 10 contiguous nucleobases that are at least 90% complementary to a segment of equal length within 10 nucleobases , or
said oligonucleotide is at positions 374, 661, 765, 837, 1149, 1150, 1176, 1347, 1598, 1629, 1760, 1752, 1795, 1775, 1793, 1799, 2879, 3008, 3114, or 3168 of SEQ ID NO: 3526 at least 10 contiguous nucleobases that are at least 90% complementary to a portion of equal length within 10 nucleobases of any one of; and at least the nucleobase sequence of An oligonucleotide or compound in which one nucleoside linkage is a modified internucleoside linkage.
前記オリゴヌクレオチドが、配列番号３５２６の位置６５５～６６５、６６０～６７０、６６５～６７５、または６７０～６８０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、
前記オリゴヌクレオチドが、配列番号３５２６の位置１３４０～１３５０、１３４５～１３５５、１３５０～１３６０、１３５５～１３６５、または１３６０～１３７０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、
前記オリゴヌクレオチドが、配列番号３５２６の位置１７４０～１７５０、１７４５～１７５５、１７５０～１７６０、１７５５～１７６５、１７６０～１７７０、１７６５～１７７５、１７７０～１７８０、１７７５～１７８５、１７８０～１７９０、１７８５～１７９５、１７９０～１８００、１７９５～１８０５、１８００～１８１０、または１８０５～１８１５のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、
前記オリゴヌクレオチドが、配列番号３５２６の位置３１１０～３１２０、３１１５～３１２５、３１２０～３１３０、３１２５～３１３５、３１３０～３１４０、３１３５～３１４５、３１４０～３１５０、３１４５～３１５５、３１５０～３１６０、３１５５～３１６５、３１６０～３１７０、３１６５～３１７５、３１７０～３１８０のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１０個の連続する核酸塩基を含む、
前記オリゴヌクレオチドが、配列番号３５２６の位置３７４、６６１、７６５、８３７、１３４７、１６２９、２８７９、３００８、３１６８、１７６０、１７５２、１７９５、１７７５、６５５～６８０、１３４０～１３７０、１７４０～１８１５、または３１１０～３１７１のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１１、１２、１３、１４、１５、１６、１７、１８、または１９個の連続する核酸塩基を含む、あるいは
前記オリゴヌクレオチドが、配列番号３５２６の位置６５５～６８０、１３４０～１３７、１７４０～１８１５、または３１１０～３１７５のうちのいずれか１つ内の核酸塩基の等しい長さの部分に相補的である少なくとも１１、１２、１３、１４、１５、１６、１７、１８、または１９個の連続する核酸塩基を含む、
請求項７に記載のオリゴヌクレオチドまたは化合物。 at least 10 stretches wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-680, 1340-137, 1740-1815, or 3110-3175 of SEQ ID NO:3526 comprising a nucleobase that
at least 10 wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-665, 660-670, 665-675, or 670-680 of SEQ ID NO:3526 containing consecutive nucleobases,
said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 1340-1350, 1345-1355, 1350-1360, 1355-1365, or 1360-1370 of SEQ ID NO:3526 at least 10 contiguous nucleobases of
wherein said oligonucleotide comprises positions 1740-1750, 1745-1755, 1750-1760, 1755-1765, 1760-1770, 1765-1775, 1770-1780, 1775-1785, 1780-1790, 1785-1795 of SEQ ID NO: 3526; comprising at least 10 contiguous nucleobases complementary to an equal length portion of nucleobases within any one of 1790-1800, 1795-1805, 1800-1810, or 1805-1815;
wherein the oligonucleotide is at positions 3110-3120, 3115-3125, 3120-3130, 3125-3135, 3130-3140, 3135-3145, 3140-3150, 3145-3155, 3150-3160, 3155-3165 of SEQ ID NO: 3526; at least 10 contiguous nucleobases complementary to an equal length portion of nucleobases within any one of 3160-3170, 3165-3175, 3170-3180;
said oligonucleotide is at position 374, 661, 765, 837, 1347, 1629, 2879, 3008, 3168, 1760, 1752, 1795, 1775, 655-680, 1340-1370, 1740-1815, or 3110 of SEQ ID NO: 3526 at least 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous nucleobases that are complementary to an equal length portion of the nucleobases within any one of -3171 contains or
at least 11 wherein said oligonucleotide is complementary to an equal length portion of the nucleobases within any one of positions 655-680, 1340-137, 1740-1815, or 3110-3175 of SEQ ID NO:3526 , 12, 13, 14, 15, 16, 17, 18, or 19 contiguous nucleobases;
8. An oligonucleotide or compound according to claim 7 .
ａ．連結したデオキシリボヌクレオシド、２’－フルオロアラビノ核酸（ＦＡＮＡ）、及びフルオロシクロヘキセン核酸（Ｆ－ＣｅＮＡ）のうちの１つ以上を含むギャップセグメント、
ｂ．連結したヌクレオシドを含む５’ウィングセグメント、及び
ｃ．連結したヌクレオシドを含む３’ウィングセグメントを含み、
前記ギャップセグメントが、前記５’ウィングセグメントと前記３’ウィングセグメントとの間に配置された配列番号１～３５２５のうちのいずれか１つの等しい長さの部分と少なくとも８０％の同一性を有する少なくとも８つの連続する核酸塩基の領域を含み、前記５’ウィングセグメント及び前記３’ウィングセグメントがそれぞれ、少なくとも２つの連結したヌクレオシドを含み、各々のウィングセグメントの少なくとも１つのヌクレオシドが、修飾糖を含む、請求項１、４、７、または８のいずれか１項に記載のオリゴヌクレオチドまたは化合物。 The oligonucleotide is
a. gap segments comprising one or more of linked deoxyribonucleosides, 2′-fluoroarabinonucleic acids (FANA), and fluorocyclohexene nucleic acids (F-CeNA);
b. a 5' wing segment comprising linked nucleosides, and
c. comprising a 3' wing segment comprising linked nucleosides;
at least the gap segment has at least 80% identity with an equal length portion of any one of SEQ ID NOs: 1-3525 located between the 5′ wing segment and the 3′ wing segment; comprising a region of 8 contiguous nucleobases, wherein said 5′ wing segment and said 3′ wing segment each comprise at least two linked nucleosides, wherein at least one nucleoside of each wing segment comprises a modified sugar; 9. The oligonucleotide or compound of any one of claims 1, 4, 7 , or 8 .
ｂ）前記５’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、ホスホロチオエートヌクレオシド間結合を介して連結され、前記３’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、ホスホロチオエートヌクレオシド間結合を介して連結され、前記ギャップセグメントのヌクレオシド間結合のうちの少なくとも１つが、修飾ヌクレオシド間結合である、
請求項１１に記載のオリゴヌクレオチドまたは化合物。 a) at least two linked nucleosides of said 5' wing segment are linked via phosphodiester internucleoside linkages and at least two linked nucleosides of said 3' wing segment are linked via phosphodiester internucleoside linkages; and at least one of the internucleoside linkages of said gap segment is a modified internucleoside linkage, or
b) said at least two linked nucleosides of said 5' wing segment are linked via phosphorothioate internucleoside linkages and said at least two linked nucleosides of said 3' wing segment are linked via phosphorothioate internucleoside linkages; and at least one of the internucleoside linkages of the gap segment is a modified internucleoside linkage.
12. An oligonucleotide or compound according to claim 11 .
ｂ）前記核酸塩基配列の少なくとも２つ、３つ、または４つのヌクレオシド間結合がホスホロチオエートヌクレオシド間結合である、
請求項１０に記載のオリゴヌクレオチドまたは化合物。 a) at least two, three, or four internucleoside linkages of said nucleobase sequence are phosphodiester internucleoside linkages, or
b) at least two, three, or four internucleoside linkages of said nucleobase sequence are phosphorothioate internucleoside linkages,
11. An oligonucleotide or compound according to claim 10 .
ｂ）前記ギャップセグメントのヌクレオシド塩基間の少なくとも１つ、２つ、３つ、または４つヌクレオシド間結合が、ホスホロチオエートヌクレオシド間結合である、かつ／あるいは
ｃ）前記核酸塩基配列の少なくとも２つのヌクレオシド間結合が修飾ヌクレオシド間結合である、
請求項１０に記載のオリゴヌクレオチドまたは化合物。 a) at least one, two, three, or four internucleoside linkages between nucleoside bases of said gap segment are phosphodiester internucleoside linkages,
b) at least one, two, three, or four internucleoside linkages between nucleoside bases of said gap segment are phosphorothioate internucleoside linkages, and/or
c) at least two internucleoside linkages of said nucleobase sequence are modified internucleoside linkages,
11. An oligonucleotide or compound according to claim 10 .
ｂ）前記核酸塩基配列の全てのヌクレオシド間結合がホスホロチオエート結合である、
請求項１５に記載のオリゴヌクレオチドまたは化合物。 a) the modified internucleoside linkages of said nucleobase sequence are phosphorothioate linkages, and/or
b) all internucleoside linkages of said nucleobase sequence are phosphorothioate linkages,
16. An oligonucleotide or compound according to claim 15 .
ｂ）前記３’ウィングセグメントの前記少なくとも２つの連結したヌクレオシドが、修飾ヌクレオシド間結合を介して連結されている、
請求項１０に記載のオリゴヌクレオチドまたは化合物。 a) at least two linked nucleosides of said 5' wing segment are linked via modified internucleoside linkages, or
b) said at least two linked nucleosides of said 3' wing segment are linked via a modified internucleoside linkage;
11. An oligonucleotide or compound according to claim 10 .
前記オリゴヌクレオチドが、５’末端にホスホロチオエートヌクレオシド間結合を介して連結された３つの連続するヌクレオシド塩基を含み、３’末端にホスホロチオエートヌクレオシド間結合を介して連結された３つの連続するヌクレオシド塩基を含む、または
前記オリゴヌクレオチドが、ホスホロチオエートヌクレオシド間結合を介して連結された５つの連続するヌクレオシド塩基を含み、前記５つの連続するヌクレオシド塩基のそれぞれが２’－Ｏ－メトキシエチルヌクレオシドである、
請求項１～８、１１、１３～１８、及び２０～２３のいずれか１項に記載のオリゴヌクレオチドまたは化合物。 said oligonucleotide comprises one or more 2′-O-methoxyethyl nucleosides linked via phosphorothioate internucleoside linkages;
The oligonucleotide comprises three consecutive nucleoside bases linked via phosphorothioate internucleoside linkages at the 5' end and three consecutive nucleoside bases linked via phosphorothioate internucleoside linkages at the 3' end. ,or
said oligonucleotide comprises 5 consecutive nucleoside bases linked via phosphorothioate internucleoside linkages, each of said 5 consecutive nucleoside bases being a 2′-O-methoxyethyl nucleoside;
24. The oligonucleotide or compound of any one of claims 1-8, 11, 13-18, and 20-23 .
ｂ）前記ギャップセグメントが、ホスホロチオエートヌクレオシド間結合を介して連結された５つの連続するヌクレオシド塩基を含み、前記５’ウィングセグメントが、少なくとも１つのホスホロチオエートヌクレオシド間結合を含み、前記３’ウィングセグメントが、少なくとも１つのホスホロチオエートヌクレオシド間結合を含む、
請求項１９に記載のオリゴヌクレオチドまたは化合物。 a) said gap segment comprises a phosphorothioate internucleoside linkage, said 5' wing segment comprises two consecutive nucleoside bases linked via phosphodiester nucleoside linkages, and said 3' wing segment comprises a phosphodiester nucleoside linkage; comprising two consecutive nucleoside bases linked via a bond, or
b) said gap segment comprises five consecutive nucleoside bases linked via phosphorothioate internucleoside linkages, said 5' wing segment comprises at least one phosphorothioate internucleoside linkage, said 3' wing segment comprises: comprising at least one phosphorothioate internucleoside linkage;
20. An oligonucleotide or compound according to claim 19 .
前記オリゴヌクレオチドが、ｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及びｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓのうちのいずれかのヌクレオシド間結合を含み、式中、ｓ＝ホスホロチオエート結合、及びｏ＝ホスホジエステル結合である、または
前記オリゴヌクレオチドが、それぞれ以下のパターン
ａ）ｄ２０とｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｂ）ｅｅｅｅｅ－ｄ１０－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｃ）ｅｅｅｅｅ－ｄ１２－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｄ）ｅｅｅｅｅ－ｄ８－ｅｅｅｅｅとｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及び
ｅ）ｅｅｋｋ－ｄ８－ｋｋｅｅｅとｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ
のうちのいずれかの糖修飾とヌクレオシド間結合の組み合わせを含み、式中、ｓ＝ホスホロチオエート結合、ｏ＝ホスホジエステル結合、ｅ＝２’－Ｏ－メトキシエチルヌクレオシド；ｄ＝２’－デオキシヌクレオシド；ｋ＝ロックド核酸（ＬＮＡ）である、
請求項１～８及び１１のいずれか１項に記載のオリゴヌクレオチドまたは化合物。 wherein the oligonucleotide comprises sugar modifications in any of the following patterns: eeeee-d10-eeeeee, d20, eeeee-d12-eeeeee, eeeee-d8-eeeee, and eekk-d8-kkeee, wherein e=2 d = 2'-deoxynucleoside; k = locked nucleic acid (LNA), constrained methoxyethyl (cMOE) nucleoside, constrained ethyl (cET) nucleoside, or peptide nucleic acid (PNA).
said oligonucleotide comprises an internucleoside linkage of any of ssssssssssssssssss, ssssssssssssssssssss, sooossssssssssss, and soosssssssssssooss, wherein s = phosphorothioate linkage and o = phosphodiester linkage, or
Each of the oligonucleotides has the following patterns
a) d20 and ssssssssssssssssssss,
b) eeeee-d10-eeeee and sssssssssssssssssss,
c) eeeee-d12-eeeee and sssssssssssssssssss, d) eeeee-d8-eeeee and sooosssssssssooss, and
e) eekk-d8-kkeee and soosssssssssooss
wherein s = phosphorothioate linkage, o = phosphodiester linkage, e = 2'-O-methoxyethylnucleoside; d = 2'-deoxynucleoside; k = locked nucleic acid (LNA)
An oligonucleotide or compound according to any one of claims 1-8 and 11 .
ａ）ｄ２０とｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、
ｂ）ｅｅｅｅｅ－ｄ１２－ｅｅｅｅｅとｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓｓ、ｃ）ｅｅｅｅｅ－ｄ８－ｅｅｅｅｅとｓｏｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、
ｄ）ｅｅｋｋ－ｄ８－ｋｋｅｅｅ及びｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ、及び
ｅ）ｅｅｋｋ－ｄ８－ｋｋｅｅｅ及びｓｏｏｓｓｓｓｓｓｓｓｓｏｏｓｓ。 The oligonucleotides each contain a combination of sugar modifications and internucleoside linkages in one of the following patterns , where s = phosphorothioate linkage, o = phosphodiester linkage, e = 2'-O-methoxyethyl nucleoside. d = 2'-deoxynucleoside; k = locked nucleic acid (LNA) and the cytosine in said oligonucleotide is unmodified cytosine. or compound :
a) d20 and ssssssssssssssssssss,
b) eeeee-d12-eeeee and sssssssssssssssssss, c) eeeee-d8-eeeee and sooosssssssssooss ,
d ) eekk-d8-kkeee and soosssssssssooss , and
e) eekk-d8-kkeee and soosssssssssooss .
前記一塩基多型が、、配列番号３５２６に示される配列の１１１２位のＣからＧ、配列番号３５２６に示される配列の２８４５位のＣからＴ、及び配列番号３５２６に示される配列の８８５位のＧからＴからなる群から選択される、
請求項３６に記載のオリゴヌクレオチドまたは化合物。 The single nucleotide polymorphism is selected from the group consisting of rs397515403, rs397515402, rs587777264, rs397515404, rs866242631, rs886043455, rs397515407, and rs397515406, or
The single nucleotide polymorphism is C to G at position 1112 in the sequence shown in SEQ ID NO: 3526, C to T at position 2845 in the sequence shown in SEQ ID NO: 3526, and position 885 in the sequence shown in SEQ ID NO: 3526 selected from the group consisting of G through T;
37. An oligonucleotide or compound according to claim 36 .
The pharmaceutical composition of any one of claims 40-42 , wherein said subject is a human.
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- 2019-12-20 AU AU2019406186A patent/AU2019406186A1/en not_active Abandoned
- 2019-12-20 EP EP19842512.6A patent/EP3898977A1/en active Pending
- 2019-12-20 US US17/415,164 patent/US20220056455A1/en active Pending
- 2019-12-20 JP JP2021535662A patent/JP2022515744A/en not_active Withdrawn
- 2019-12-20 CA CA3123617A patent/CA3123617A1/en active Pending
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