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Description
塩基性条件下で単量体９及び１８を組み合わせることにより、ホスフィネート連結二量体１９を得る。酸媒介性及びパールマン触媒による脱保護後のさらなるホスファンアミン官能化により、二量体２２を得る。
本発明は、以下の態様を含む。
［項１］ ５’末端、３’末端及びシード領域を有するオリゴヌクレオチドであって、アレル多型を含む遺伝子の領域と相補的であり、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、オリゴヌクレオチド。
［項２］ 前記オリゴヌクレオチドは、ＲＮＡである、項１に記載のオリゴヌクレオチド。
［項３］ 式：
［化１］
［項４］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項３に記載のＲＮＡ。
［項５］ ｓｉＲＮＡ、ｍｉＲＮＡ、ｓｈＲＮＡ、ＣＲＩＳＰＲガイド、ＤＮＡ、アンチセンスオリゴヌクレオチド（ＡＳＯ）、ギャップマー、ミックスマー、ｍｉＲＮＡ阻害剤、スプライススイッチングオリゴヌクレオチド（ＳＳＯ）、ホスホロジアミダートモルホリノオリゴマー（ＰＭＯ）及びペプチド核酸（ＰＮＡ）からなる群から選択される、項１に記載のオリゴヌクレオチド。
［項６］ ＡＳＯ又は二重鎖ＲＮＡ（ｄｓＲＮＡ）である、項１に記載のオリゴヌクレオチド。
［項７］ アレル多型を含む前記遺伝子の前記領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、前記５’末端から２～６位における前記ＳＮＰ位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する前記ＭＭ位置ヌクレオチドを含む、項６に記載のｄｓＲＮＡ。
［項８］ 前記ＳＮＰ位置ヌクレオチドは、前記５’末端から２位にある、項７に記載のｄｓＲＮＡ。
［項９］ 前記ＳＮＰ位置ヌクレオチドは、前記５’末端から４位にある、項７に記載のｄｓＲＮＡ。
［項１０］ 前記ＳＮＰ位置ヌクレオチドは、前記第１の鎖の前記５’末端から６位にある、項７に記載のｄｓＲＮＡ。
［項１１］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドの２ヌクレオチド以内又は３ヌクレオチド以内に位置する、項７～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１２］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドの４ヌクレオチド以内に位置する、項７～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１３］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドの６ヌクレオチド以内に位置する、項７～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１４］ 平滑末端である、項７～１３のいずれか一項に記載のｄｓＲＮＡ。
［項１５］ 少なくとも１つの一本鎖ヌクレオチドオーバーハングを含む、項７～１３のいずれか一項に記載のｄｓＲＮＡ。
［項１６］ 天然に存在するヌクレオチドを含む、項７～１５のいずれか一項に記載のｄｓＲＮＡ。
［項１７］ 少なくとも１つの修飾ヌクレオチドを含む、項７～１６のいずれか一項に記載のｄｓＲＮＡ。
［項１８］ 各ヌクレオチドは、修飾される、項７～１５のいずれか一項に記載のｄｓＲＮＡ。
［項１９］ 前記少なくとも１つの修飾ヌクレオチドは、２’－Ｏ－メチ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、コレステリル誘導体に連結された末端ヌクレオチド及びドデカン酸ビスデシルアミド基に連結された末端ヌクレオチドからなる群から選択される、項１７に記載のｄｓＲＮＡ。
［項２０］ 前記修飾ヌクレオチドは、２’－デオキシ－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、脱塩基ヌクレオチド、２’－アミノ修飾ヌクレオチド、２’－アルキル修飾ヌクレオチド、モルホリノヌクレオチド、ホスホロアミダート及び非天然塩基を含むヌクレオチドからなる群から選択される、項１７に記載のｄｓＲＮＡ。
［項２１］ 少なくとも１つの２’－Ｏ－メチル修飾ヌクレオチド及び５’－ホスホロチオエート基を含む、項７～２０のいずれか一項に記載のｄｓＲＮＡ。
［項２２］ 前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含む、項７～２１のいずれか一項に記載のｄｓＲＮＡ。
［項２３］ 前記第１の鎖は、前記ＳＮＰ位置ヌクレオチドのいずれかの側で２’－Ｏ－メチル修飾ヌクレオチドを含む、項２２に記載のｄｓＲＮＡ。
［項２４］ 疎水性部分を含む、項７～２３のいずれか一項に記載のｄｓＲＮＡ。
［項２５］ 前記アレル多型を含む遺伝子の前記領域は、配列番号１～１０からなる群から選択される核酸配列を含む、項７～２４のいずれか一項に記載のｄｓＲＮＡ。
［項２６］ 前記第１の鎖は、ＵＵＣＵＧＵＡＧＣＡＵＣＡＧＣＵＵＣＵＣを含む、項７～２５のいずれか一項に記載のｄｓＲＮＡ。
［項２７］ 二重鎖ＲＮＡ（ｄｓＲＮＡ）であって、
アレル多型を含む遺伝子の領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、５’末端から４位における一塩基多型（ＳＮＰ）位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記５’末端から７位に位置するミスマッチ（ＭＭ）位置ヌクレオチドを含む、二重鎖ＲＮＡ（ｄｓＲＮＡ）。
［項２８］ 式：
［化２］
［項２９］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項２８に記載の二分岐オリゴヌクレオチド化合物。
［項３０］ 前記第１の鎖は、前記ＳＮＰ位置ヌクレオチドのいずれかの側で２’－Ｏ－メチル修飾ヌクレオチドを含む、項２７に記載のｄｓＲＮＡ。
［項３１］ 前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含む、項３０に記載のｄｓＲＮＡ。
［項３２］ ５’－ホスホロチオエート基を含む、項３１に記載のｄｓＲＮＡ。
［項３３］ アレル多型を含む前記遺伝子は、ハンチンチン（ｈｔｔ）遺伝子である、項２７に記載のｄｓＲＮＡ。
［項３４］ 前記アレル多型を含む遺伝子の前記領域は、配列番号１～１０からなる群から選択される核酸配列を含む、項２７に記載のｄｓＲＮＡ。
［項３５］ 前記第１の鎖は、ＵＵＣＵＧＵＡＧＣＡＵＣＡＧＣＵＵＣＵＣを含む、項２７に記載のｄｓＲＮＡ。
［項３６］ 二重鎖ＲＮＡ（ｄｓＲＮＡ）であって、
アレル多型を含む遺伝子の領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、５’末端から６位における一塩基多型（ＳＮＰ）位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記５’末端から１１位に位置するミスマッチ（ＭＭ）位置ヌクレオチドを含む、二重鎖ＲＮＡ（ｄｓＲＮＡ）。
［項３７］ 式：
［化３］
［項３８］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項３７に記載の二分岐オリゴヌクレオチド化合物。
［項３９］ 前記第１の鎖は、前記ＳＮＰ位置ヌクレオチドのいずれかの側で２’－Ｏ－メチル修飾ヌクレオチドを含む、項３６に記載のｄｓＲＮＡ。
［項４０］ 前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含む、項３９に記載のｄｓＲＮＡ。
［項４１］ ５’－ホスホロチオエート基を含む、項３６に記載のｄｓＲＮＡ。
［項４２］ アレル多型を含む前記遺伝子は、ハンチンチン（ｈｔｔ）遺伝子である、項３６に記載のｄｓＲＮＡ。
［項４３］ 前記アレル多型を含む遺伝子の前記領域は、配列番号１～１０からなる群から選択される核酸配列を含む、項３６に記載のｄｓＲＮＡ。
［項４４］ 前記第１の鎖は、ＵＵＣＵＧＵＡＧＣＡＵＣＡＧＣＵＵＣＵＣを含む、項３６に記載のｄｓＲＮＡ。
［項４５］ 項１～４４のいずれか一項に記載のＲＮＡ及び薬学的に許容される担体を含む医薬組成物。
［項４６］ 細胞におけるアレル多型を含む遺伝子の発現を阻害する方法であって、前記細胞を、項１～４４のいずれか一項に記載のＲＮＡと接触させることを含む方法。
［項４７］ アレル多型を含む遺伝子によって特徴付けられるか又は引き起こされる疾患又は障害の治療を、それを必要とする対象において行う方法であって、治療有効量の、アレル多型を含む遺伝子の領域と相補的である、５’末端、３’末端及びシード領域を有するＲＮＡを対象に投与することを含み、前記ＲＮＡは、
前記アレル多型と相補的である、前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、方法。
［項４８］ 前記ＲＮＡは、式：
［化４］
［項４９］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項４８に記載の二分岐オリゴヌクレオチド化合物。
［項５０］ 前記ＲＮＡは、ＡＳＯ又はｄｓＲＮＡである、項４７に記載の方法。
［項５１］ 前記ｄｓＲＮＡは、
アレル多型を含む前記遺伝子の前記領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、前記５’末端から２～６位における前記ＳＮＰ位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する前記ＭＭ位置ヌクレオチドを含む、項４７に記載の方法。
［項５２］ 前記ｄｓＲＮＡは、前記対象の脳に投与される、項５１に記載の方法。
［項５３］ 前記ｄｓＲＮＡは、線条体内注入によって投与される、項５１に記載の方法。
［項５４］ 線条体における前記遺伝子の発現の減少は、達成される、項５２に記載の方法。
［項５５］ 皮質における前記遺伝子の発現の減少は、達成される、項５２に記載の方法。
［項５６］ アレル多型を含む前記遺伝子は、ハンチンチン（ｈｔｔ）遺伝子である、項４７～５５のいずれか一項に記載の方法。
［項５７］ 前記疾患は、ハンチントン病である、項４７～５６のいずれか一項に記載の方法。
［項５８］ 前記ＳＮＰ位置ヌクレオチドは、前記ＲＮＡの前記５’末端から２、４又は６位に位置し、及び前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する、項１に記載のＲＮＡ。
［項５９］ ２つのＲＮＡを含む二分岐オリゴヌクレオチド化合物であって、前記ＲＮＡは、リンカー、スペーサー及び分岐点から選択される１つ以上の部分によって互いに連結され、各ＲＮＡは、５’末端、３’末端及びシード領域を有し、各ＲＮＡは、アレル多型を含む遺伝子の領域と相補的であり、各ＲＮＡは、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、二分岐オリゴヌクレオチド化合物。
［項６０］ 前記ＲＮＡは、式：
［化５］
［項６１］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項６０に記載の二分岐オリゴヌクレオチド化合物。
［項６２］ ｈｓｉ－ＲＮＡ構造を有する、項５９に記載の二分岐オリゴヌクレオチド。
［項６３］ 前記ＳＮＰ位置ヌクレオチドは、ｒｓ３６３１２５、ｒｓ３６２２７３、ｒｓ３６２３０７、ｒｓ３６２３３６、ｒｓ３６２３３１、ｒｓ３６２２７２、ｒｓ３６２３０６、ｒｓ３６２２６８、ｒｓ３６２２６７及びｒｓ３６３０９９からなる群から選択されるｈｔｔ ＳＮＰのアレル多型と相補的である、項５９に記載の二分岐オリゴヌクレオチド化合物。
［項６４］ 前記ＳＮＰ位置ヌクレオチドは、ｒｓ３６３１２５、ｒｓ３６２２７３、ｒｓ３６２３０７、ｒｓ３６２３３６、ｒｓ３６２３３１、ｒｓ３６２２７２、ｒｓ３６２３０６、ｒｓ３６２２６８、ｒｓ３６２２６７及びｒｓ３６３０９９からなる群から選択されるｈｔｔ ＳＮＰのアレル多型と相補的である、項１に記載のＲＮＡ。
［項６５］ ホスフェート、ビニルホスホネート、Ｃ５－メチル（Ｒ、又はＳ、又はラセミ）、ビニル上のＣ５－メチル及び還元ビニルからなる群から選択される５’安定化部分をさらに含む、項１に記載のＲＮＡ。
［項６６］ アルキル鎖、ビタミン、ペプチド、スフィンゴ糖脂質、多価不飽和脂肪酸、セコステロイド、ステロイドホルモン及びステロイド脂質からなる群から選択されるコンジュゲート部分をさらに含む、項１に記載のＲＮＡ。
［項６７］ アレル多型を含む遺伝子の領域と相補的である、５’末端、３’末端及びシード領域を有する核酸であって、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）
を含む、核酸。
［項６８］ 式：
［化６］
［項６９］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項６８に記載の二分岐オリゴヌクレオチド化合物。
［項７０］ アレル多型を含む遺伝子の領域と相補的である、５’末端、３’末端及びシード領域を有する核酸であって、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）
を含む、核酸。
［項７１］ 式：
［化７］
［項７２］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項７１に記載の二分岐オリゴヌクレオチド化合物。
［項７３］ アレル多型を含む遺伝子の領域と相補的である、５’末端、３’末端及びシード領域を有する核酸であって、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＭＭ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｙ）であって、各Ｙは、前記ＭＭ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｙ）
を含む、核酸。
［項７４］ 式：
［化８］
［項７５］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項７４に記載の二分岐オリゴヌクレオチド化合物。
［項７６］ Ｘは、２’－Ｏ－メチル（２’－ＯＭｅ）、２’－フルオロ（２’－Ｆ）、２’－リボ、２’－デオキシリボ、２’－Ｆ－４’－チオアラビノ（２’－Ｆ－ＡＮＡ）、２－Ｏ－（２－メトキシエチル）（２’－ＭＯＥ）、４’－Ｓ－ＲＮＡ、ロックド核酸（ＬＮＡ）、４’－Ｓ－Ｆ－ＡＮＡ、２’－Ｏ－アリル、２’－Ｏ－エチルアミン、２－シアノエチル－ＲＮＡ（ＣＮｅｔ－ＲＮＡ）、トリシクロ－ＤＮＡ、シクロヘキシル核酸（ＣｅＮＡ）、アラビノ核酸（ＡＮＡ）及びヘキシトール核酸（ＨＮＡ）からなる群から選択される糖修飾を含む、項７０に記載の核酸。
［項７７］ Ｙは、２’－ＯＭｅ、２’－Ｆ、２’－リボ、２’－デオキシリボ、２’－Ｆ－ＡＮＡ、２’－ＭＯＥ、４’－Ｓ－ＲＮＡ、ＬＮＡ、４’－Ｓ－Ｆ－ＡＮＡ、２’－Ｏ－アリル、２’－Ｏ－エチルアミン、ＣＮｅｔ－ＲＮＡ、トリシクロ－ＤＮＡ、ＣｅＮＡ、ＡＮＡ及びＨＮＡからなる群から選択される糖修飾を含む、項７３に記載の核酸。
［項７８］ Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近又は前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置する、項７０に記載の核酸。
［項７９］ Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近及び前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置する、項７０に記載の核酸。
［項８０］ Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近又は前記ＭＭ位置ヌクレオチドに対する３’の直近に位置する、項７３に記載の核酸。
［項８１］ Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近及び前記ＭＭ位置ヌクレオチドに対する３’の直近に位置する、項７３に記載の核酸。
［項８２］ 前記ＳＮＰ位置ヌクレオチドは、前記５’末端から２位～６位に存在する、項７０又は７３に記載の核酸。
［項８３］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置する、項７０又は７３に記載の核酸。
［項８４］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する、項７０又は７３に記載の核酸。
［項８５］ アレル多型を含む遺伝子の領域と相補的である、５’末端、３’末端及びシード領域を有する核酸であって、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）；及び
前記ＭＭ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｙ）であって、各Ｙは、前記ＭＭ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｙ）
を含む、核酸。
［項８６］ 式：
［化９］
［項８７］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項８６に記載の二分岐オリゴヌクレオチド化合物。
［項８８］ Ｘは、２’－ＯＭｅ、２’－Ｆ、２’－リボ、２’－デオキシリボ、２’－Ｆ－ＡＮＡ、２’－ＭＯＥ、４’－Ｓ－ＲＮＡ、ＬＮＡ、４’－Ｓ－Ｆ－ＡＮＡ、２’－Ｏ－アリル、２’－Ｏ－エチルアミン、ＣＮｅｔ－ＲＮＡ、トリシクロ－ＤＮＡ、ＣｅＮＡ、ＡＮＡ及びＨＮＡからなる群から選択される糖修飾を含む、項８５に記載の核酸。
［項８９］ Ｙは、２’－ＯＭｅ、２’－Ｆ、２’－リボ、２’－デオキシリボ、２’－Ｆ－ＡＮＡ、２’－ＭＯＥ、４’－Ｓ－ＲＮＡ、ＬＮＡ、４’－Ｓ－Ｆ－ＡＮＡ、２’－Ｏ－アリル、２’－Ｏ－エチルアミン、ＣＮｅｔ－ＲＮＡ、トリシクロ－ＤＮＡ、ＣｅＮＡ、ＡＮＡ及びＨＮＡからなる群から選択される糖修飾を含む、項８５に記載の核酸。
［項９０］ Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近又は前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置する、項８５に記載の核酸。
［項９１］ Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近及び前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置する、項８５に記載の核酸。
［項９２］ Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近又は前記ＭＭ位置ヌクレオチドに対する３’の直近に位置する、項８５に記載の核酸。
［項９３］ Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近及び前記ＭＭ位置ヌクレオチドに対する３’の直近に位置する、項８５に記載の核酸。
［項９４］ 前記ＳＮＰ位置ヌクレオチドは、前記５’末端から２位～６位に存在する、項８５に記載の核酸。
［項９５］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置する、項８５に記載の核酸。
［項９６］ 前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する、項８５に記載の核酸。
［項９７］ Ｘ及びＹは、同じである、項７０、７３又は８５のいずれか一項に記載の核酸。
［項９８］ Ｘ及びＹは、異なる、項７０、７３又は８５のいずれか一項に記載の核酸。
［項９９］ ２つ以上の核酸配列を含む二分岐オリゴヌクレオチド化合物であって、前記核酸配列（Ｎ）は、リンカー（Ｌ）、スペーサー（Ｓ）及び任意選択的に分岐点（Ｂ）から選択される１つ以上の部分によって互いに連結され、
各核酸配列は、二重鎖であり、且つセンス鎖及びアンチセンス鎖を含み、前記センス鎖及び前記アンチセンス鎖は、それぞれ５’末端及び３’末端を有し、前記センス鎖及び前記アンチセンス鎖は、それぞれ１つ以上の化学修飾されたヌクレオチドを含み、
各アンチセンス鎖は、シード領域を有し、各アンチセンス鎖は、アレル多型を含む遺伝子の領域と相補的であり、各アンチセンス鎖は、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、二分岐オリゴヌクレオチド化合物。
［項１００］ 前記ＲＮＡは、式：
［化１０］
［項１０１］ ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、項１００に記載の二分岐オリゴヌクレオチド化合物。
［項１０２］ 前記センス鎖及び前記アンチセンス鎖は、それぞれ＞８０％の化学修飾されたヌクレオチドを含む、項９９に記載の二分岐オリゴヌクレオチド化合物。
［項１０３］ 前記センス及びアンチセンス鎖の前記５’末端から１及び２位での前記ヌクレオチドは、ホスホロチオエート結合を介して隣接ヌクレオチドに連結される、項９９に記載の二分岐オリゴヌクレオチド化合物。
［項１０４］ 各アンチセンス鎖は、少なくとも１５個の連続したヌクレオチドを含み、各センス鎖は、少なくとも１５個の連続したヌクレオチドを含み、且つ前記アンチセンス鎖に対して相補性を有する、項９９に記載の二分岐オリゴヌクレオチド化合物。
［項１０５］ 前記分岐オリゴヌクレオチド化合物の末端５’位に結合された疎水性部分をさらに含む、項９９に記載の二分岐オリゴヌクレオチド化合物。
［項１０６］ 各二重鎖核酸配列は、前記センス鎖又は前記アンチセンス鎖の前記３’末端又は前記５’末端でのリンカー、スペーサー又は分岐点に独立して連結される、項９９に記載の二分岐オリゴヌクレオチド化合物。
［項１０７］ 前記ＳＮＰ位置ヌクレオチドは、ｒｓ３６３１２５、ｒｓ３６２２７３、ｒｓ３６２３０７、ｒｓ３６２３３６、ｒｓ３６２３３１、ｒｓ３６２２７２、ｒｓ３６２３０６、ｒｓ３６２２６８、ｒｓ３６２２６７及びｒｓ３６３０９９からなる群から選択されるｈｔｔ ＳＮＰのアレル多型と相補的である、項９９に記載の二分岐オリゴヌクレオチド化合物。
Combining monomers 9 and 18 under basic conditions gives the phosphinate-linked dimer 19. Further phosphanamine functionalization after acid-mediated and Pearlman-catalyzed deprotection gives the dimer 22.
The present invention includes the following aspects.
[Claim 1] An oligonucleotide having a 5' end, a 3' end and a seed region, which is complementary to a gene region containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and
a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene
an oligonucleotide.
[Item 2] The oligonucleotide according to item 1, wherein the oligonucleotide is RNA.
[Term 3] Formula:
[Chemical 1]
[Item 4] The RNA according to Item 3, wherein the VP motif is inserted next to the nucleotide at the SNP position or next to the nucleotide at the MM position.
[Item 5] siRNA, miRNA, shRNA, CRISPR guide, DNA, antisense oligonucleotide (ASO), gapmer, mixmer, miRNA inhibitor, splice switching oligonucleotide (SSO), phosphorodiamidate morpholino oligomer (PMO) and peptide nucleic acid (PNA).
[Item 6] The oligonucleotide according to Item 1, which is ASO or double-stranded RNA (dsRNA).
[Section 7] a first strand of about 15-35 nucleotides complementary to said region of said gene containing an allelic polymorphism; and
a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand
including
the first strand comprises the SNP position nucleotides at positions 2-6 from the 5' end that are complementary to the allelic polymorphism;
7. The dsRNA of paragraph 6, wherein said first strand comprises said MM position nucleotide located 2-6 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene.
[Item 8] The dsRNA according to Item 7, wherein the SNP position nucleotide is at position 2 from the 5' end.
[Item 9] The dsRNA according to Item 7, wherein the SNP position nucleotide is located at position 4 from the 5' end.
[Item 10] The dsRNA of Item 7, wherein the SNP position nucleotide is at position 6 from the 5' end of the first strand.
[Item 11] The dsRNA according to any one of items 7 to 10, wherein the nucleotide at the MM position is located within 2 nucleotides or within 3 nucleotides of the nucleotide at the SNP position.
[Item 12] The dsRNA according to any one of items 7 to 10, wherein the nucleotide at the MM position is located within 4 nucleotides of the nucleotide at the SNP position.
[Item 13] The dsRNA according to any one of items 7 to 10, wherein the nucleotide at the MM position is located within 6 nucleotides of the nucleotide at the SNP position.
[Item 14] The dsRNA of any one of items 7 to 13, which is blunt-ended.
[Item 15] The dsRNA of any one of Items 7 to 13, comprising at least one single-stranded nucleotide overhang.
[Item 16] The dsRNA of any one of Items 7 to 15, which comprises naturally occurring nucleotides.
[Item 17] The dsRNA of any one of items 7 to 16, comprising at least one modified nucleotide.
[Item 18] The dsRNA of any one of items 7 to 15, wherein each nucleotide is modified.
[Claim 19] The at least one modified nucleotide includes a 2'-O-methyl modified nucleotide, a nucleotide containing a 5'-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, and a terminal linked to a dodecanoic acid bisdecylamide group. 18. The dsRNA of paragraph 17, selected from the group consisting of nucleotides.
[Claim 20] The modified nucleotides are 2'-deoxy-2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, locked nucleotides, abasic nucleotides, 2'-amino modified nucleotides, 2'-alkyl modified nucleotides, 18. The dsRNA of paragraph 17, which is selected from the group consisting of morpholinonucleotides, phosphoramidates and nucleotides containing unnatural bases.
[Item 21] The dsRNA of any one of items 7 to 20, comprising at least one 2'-O-methyl modified nucleotide and a 5'-phosphorothioate group.
[Item 22] The dsRNA of any one of items 7 to 21, wherein the first strand comprises at least three 2'-O-methyl modified nucleotides.
[Section 23] The dsRNA of Clause 22, wherein said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides.
[Item 24] The dsRNA of any one of Items 7 to 23, which comprises a hydrophobic portion.
[Item 25] The dsRNA according to any one of Items 7 to 24, wherein the region of the gene containing the allelic polymorphism comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1 to 10.
[Section 26] The dsRNA of any one of Sections 7 to 25, wherein the first strand comprises UUCUGUAGCAUCAGCCUUCUC.
[Claim 27] A double-stranded RNA (dsRNA),
a first strand of about 15-35 nucleotides complementary to the region of the gene containing the allelic polymorphism; and
a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand
including
the first strand comprises a single nucleotide polymorphism (SNP) position nucleotide at position 4 from the 5' end that is complementary to the allelic polymorphism;
A double-stranded RNA (dsRNA) wherein said first strand comprises a mismatch (MM) position nucleotide located at position 7 from said 5' end that is mismatched with a nucleotide in said gene.
[Section 28] Formula:
[Chemical 2]
[Item 29] The biantennary oligonucleotide compound of Item 28, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
30. The dsRNA of 27, wherein said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides.
[Term 31] The dsRNA of Claim 30, wherein said first strand comprises at least three 2'-O-methyl modified nucleotides.
[Item 32] The dsRNA of Item 31, comprising a 5'-phosphorothioate group.
[Item 33] The dsRNA of Item 27, wherein the gene containing the allelic polymorphism is a huntingtin (htt) gene.
[Item 34] The dsRNA of Item 27, wherein the region of the gene containing the allelic polymorphism comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1-10.
[Item 35] The dsRNA of Item 27, wherein the first strand comprises UUCUGUAGCAUCAGCCUUCUC.
[Claim 36] A double-stranded RNA (dsRNA),
a first strand of about 15-35 nucleotides complementary to the region of the gene containing the allelic polymorphism; and
a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand
including
the first strand comprises a single nucleotide polymorphism (SNP) position nucleotide at position 6 from the 5' end that is complementary to the allelic polymorphism;
A double-stranded RNA (dsRNA) wherein said first strand comprises a mismatch (MM) position nucleotide located at position 11 from said 5' end that is mismatched with a nucleotide in said gene.
[Section 37] Formula:
[Chemical 3]
38. The biantennary oligonucleotide compound of 37, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Term 39] The dsRNA of Claim 36, wherein said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides.
[Term 40] The dsRNA of Claim 39, wherein said first strand comprises at least three 2'-O-methyl modified nucleotides.
[Item 41] The dsRNA of Item 36, comprising a 5'-phosphorothioate group.
[Item 42] The dsRNA of Item 36, wherein the gene containing the allelic polymorphism is a huntingtin (htt) gene.
[Item 43] The dsRNA of Item 36, wherein the region of the gene containing the allelic polymorphism comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1-10.
[Item 44] The dsRNA of Item 36, wherein the first strand comprises UUCUGUAGCAUCAGCCUUCUC.
[Item 45] A pharmaceutical composition comprising the RNA of any one of items 1 to 44 and a pharmaceutically acceptable carrier.
[Item 46] A method of inhibiting expression of a gene containing an allelic polymorphism in a cell, the method comprising contacting the cell with the RNA of any one of Items 1-44.
[Claim 47] A method of treating a disease or disorder characterized by or caused by a gene comprising an allelic polymorphism in a subject in need thereof, comprising a therapeutically effective amount of the gene comprising the allelic polymorphism administering to the subject an RNA having a 5′ end, a 3′ end and a seed region that are complementary to the region, the RNA comprising:
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region that is complementary to said allelic polymorphism; and
a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene
A method, including
[Section 48] The RNA has the formula:
[Chemical 4]
[Term 49] The biantennary oligonucleotide compound of Claim 48, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Item 50] The method according to Item 47, wherein the RNA is ASO or dsRNA.
[Claim 51] The dsRNA is
a first strand of about 15-35 nucleotides complementary to said region of said gene containing the allelic polymorphism; and
a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand
including
the first strand comprises the SNP position nucleotides at positions 2-6 from the 5' end that are complementary to the allelic polymorphism;
48. The method of paragraph 47, wherein said first strand comprises said MM position nucleotide located 2-6 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene.
[Term 52] The method of Claim 51, wherein said dsRNA is administered to the brain of said subject.
[Term 53] The method of Claim 51, wherein the dsRNA is administered by intrastriatal injection.
54. The method of 52, wherein the reduction of expression of said gene in the striatum is achieved.
55. The method of 52, wherein the reduction of expression of said gene in the cortex is achieved.
[Item 56] The method according to any one of Items 47 to 55, wherein the gene containing the allelic polymorphism is a huntingtin (htt) gene.
[Section 57] The method of any one of Sections 47 to 56, wherein the disease is Huntington's disease.
[Term 58] Term 1, wherein the SNP position nucleotide is located 2, 4 or 6 from the 5' end of the RNA, and the MM position nucleotide is located 2-6 nucleotides from the SNP position nucleotide. RNA as described in .
[Claim 59] A biantennary oligonucleotide compound comprising two RNAs, said RNAs linked together by one or more moieties selected from linkers, spacers and branch points, each RNA comprising a 5' end, having a 3' end and a seed region, each RNA being complementary to a region of the gene containing the allelic polymorphism, each RNA comprising:
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and
a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene
A biantennary oligonucleotide compound comprising:
[Section 60] The RNA has the formula:
[Chemical 5]
61. The biantennary oligonucleotide compound of 60, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Item 62] The biantennary oligonucleotide of Item 59, which has an hsi-RNA structure.
[Term 63] The SNP position nucleotide is complementary to an allelic polymorphism of the htt SNP selected from the group consisting of rs363125, rs362273, rs362307, rs362336, rs362331, rs362272, rs362306, rs362268, rs362267 and rs363099, Term 59 A biantennary oligonucleotide compound according to .
[Item 64] Item 1, wherein the nucleotide at the SNP position is complementary to an allelic polymorphism of the htt SNP selected from the group consisting of rs363125, rs362273, rs362307, rs362336, rs362331, rs362272, rs362306, rs362268, rs362267 and rs363099. RNA as described in .
[Item 65] Item 1, further comprising a 5' stabilizing moiety selected from the group consisting of phosphate, vinyl phosphonate, C5-methyl (R, or S, or racemic), C5-methyl on vinyl, and reduced vinyl. RNA as indicated.
[Item 66] The RNA of Item 1, further comprising a conjugate moiety selected from the group consisting of alkyl chains, vitamins, peptides, glycosphingolipids, polyunsaturated fatty acids, secosteroids, steroid hormones and steroid lipids.
[Claim 67] A nucleic acid having a 5′ end, a 3′ end and a seed region that is complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and
at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X located within 4, 3 or 2 nucleotides of said SNP position nucleotide (X )
Nucleic acids, including
[Section 68] Formula:
[Chemical 6]
69. The biantennary oligonucleotide compound of 68, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Claim 70] A nucleic acid having a 5′ end, a 3′ end and a seed region that is complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and
at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X located within 4, 3 or 2 nucleotides of said SNP position nucleotide (X )
Nucleic acids, including
[Section 71] Formula:
[Chemical 7]
72. The biantennary oligonucleotide compound of 71, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Claim 73] A nucleic acid having a 5′ end, a 3′ end and a seed region that is complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and
at least one modified nucleotide (Y) on either side of said MM position nucleotide, each Y located within 4, 3 or 2 nucleotides of said MM position nucleotide (Y )
Nucleic acids, including
[Section 74] Formula:
[Chemical 8]
75. The biantennary oligonucleotide compound of 74, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Claim 76] X is 2′-O-methyl (2′-OMe), 2′-fluoro (2′-F), 2′-ribo, 2′-deoxyribo, 2′-F-4′-thioarabino (2'-F-ANA), 2-O-(2-methoxyethyl) (2'-MOE), 4'-S-RNA, locked nucleic acid (LNA), 4'-SF-ANA, 2' -O-allyl, 2'-O-ethylamine, 2-cyanoethyl-RNA (CNet-RNA), tricyclo-DNA, cyclohexyl nucleic acid (CeNA), arabinonucleic acid (ANA) and hexitol nucleic acid (HNA); 71. The nucleic acid of Paragraph 70, comprising a sugar modification that
[Claim 77] Y is 2′-OMe, 2′-F, 2′-ribo, 2′-deoxyribo, 2′-F-ANA, 2′-MOE, 4′-S-RNA, LNA, 4′ -SF-ANA, 2'-O-allyl, 2'-O-ethylamine, CNet-RNA, tricyclo-DNA, CeNA, ANA and HNA. of nucleic acids.
[Item 78] The nucleic acid of item 70, wherein X is located immediately 5' to the nucleotide at the SNP position or immediately 3' to the nucleotide at the SNP position.
79. The nucleic acid of 70, wherein X is located immediately 5' to the nucleotide at the SNP position and immediately 3' to the nucleotide at the SNP position.
80. The nucleic acid of paragraph 73, wherein Y is located immediately 5' to the nucleotide at the MM position or immediately 3' to the nucleotide at the MM position.
81. The nucleic acid of paragraph 73, wherein Y is located immediately 5' to said nucleotide at the MM position and immediately 3' to said nucleotide at the MM position.
[Item 82] The nucleic acid according to Item 70 or 73, wherein the SNP position nucleotides are present at positions 2 to 6 from the 5' end.
[Item 83] The nucleic acid according to Item 70 or 73, wherein the MM position nucleotide is located 2-11 nucleotides from the SNP position nucleotide.
[Item 84] The nucleic acid according to Item 70 or 73, wherein the nucleotide at the MM position is located 2-6 nucleotides from the nucleotide at the SNP position.
[Claim 85] A nucleic acid having a 5′ end, a 3′ end and a seed region that is complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and
at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X located within 4, 3 or 2 nucleotides of said SNP position nucleotide (X );as well as
at least one modified nucleotide (Y) on either side of said MM position nucleotide, each Y located within 4, 3 or 2 nucleotides of said MM position nucleotide (Y )
Nucleic acids, including
[Section 86] Formula:
[Chemical 9]
[Term 87] The biantennary oligonucleotide compound of Claim 86, wherein the VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide.
[Claim 88] X is 2′-OMe, 2′-F, 2′-ribo, 2′-deoxyribo, 2′-F-ANA, 2′-MOE, 4′-S-RNA, LNA, 4′ -SF-ANA, 2'-O-allyl, 2'-O-ethylamine, CNet-RNA, tricyclo-DNA, CeNA, ANA and HNA. of nucleic acids.
[Section 89] Y is 2′-OMe, 2′-F, 2′-ribo, 2′-deoxyribo, 2′-F-ANA, 2′-MOE, 4′-S-RNA, LNA, 4′ -SF-ANA, 2'-O-allyl, 2'-O-ethylamine, CNet-RNA, tricyclo-DNA, CeNA, ANA and HNA. of nucleic acids.
[Item 90] The nucleic acid of item 85, wherein X is located immediately 5' to the nucleotide at the SNP position or immediately 3' to the nucleotide at the SNP position.
[Item 91] The nucleic acid of item 85, wherein X is located immediately 5' to the nucleotide at the SNP position and immediately 3' to the nucleotide at the SNP position.
92. The nucleic acid of 85, wherein Y is located immediately 5' to the nucleotide at the MM position or immediately 3' to the nucleotide at the MM position.
93. The nucleic acid of 85, wherein Y is located immediately 5' to said nucleotide at the MM position and immediately 3' to said nucleotide at the MM position.
[Item 94] The nucleic acid according to Item 85, wherein the SNP position nucleotides are present at positions 2 to 6 from the 5' end.
95. The nucleic acid of 85, wherein the MM position nucleotide is located 2-11 nucleotides from the SNP position nucleotide.
96. The nucleic acid of 85, wherein the MM position nucleotide is located 2-6 nucleotides from the SNP position nucleotide.
[Section 97] The nucleic acid of any one of Sections 70, 73 or 85, wherein X and Y are the same.
[Section 98] The nucleic acid of any one of Clauses 70, 73 or 85, wherein X and Y are different.
[Section 99] A biantennary oligonucleotide compound comprising two or more nucleic acid sequences, wherein said nucleic acid sequences (N) are selected from linkers (L), spacers (S) and optionally branch points (B) connected to each other by one or more moieties
Each nucleic acid sequence is double stranded and comprises a sense strand and an antisense strand, said sense strand and said antisense strand having 5′ and 3′ ends, respectively, said sense strand and said antisense strand the strands each comprise one or more chemically modified nucleotides,
Each antisense strand has a seed region, each antisense strand is complementary to a region of the gene containing the allelic polymorphism, and each antisense strand comprises
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and
a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene
A biantennary oligonucleotide compound comprising:
[Section 100] The RNA has the formula:
[Chemical 10]
[Item 101] The biantennary oligonucleotide compound of Item 100, wherein the VP motif is inserted next to the nucleotide at the SNP position or next to the nucleotide at the MM position.
102. The biantennary oligonucleotide compound of 99, wherein said sense strand and said antisense strand each comprise >80% chemically modified nucleotides.
103. The biantennary oligonucleotide compound of 99, wherein the nucleotides at positions 1 and 2 from the 5' ends of the sense and antisense strands are linked to adjacent nucleotides via phosphorothioate linkages.
[Term 104] Term 99, wherein each antisense strand comprises at least 15 contiguous nucleotides and each sense strand comprises at least 15 contiguous nucleotides and is complementary to said antisense strand. A biantennary oligonucleotide compound according to .
[Term 105] The biantennary oligonucleotide compound of paragraph 99, further comprising a hydrophobic moiety attached to the terminal 5' position of said branched oligonucleotide compound.
[Section 106] of Paragraph 99, wherein each double-stranded nucleic acid sequence is independently linked to a linker, spacer or branch point at said 3' end or said 5' end of said sense strand or said antisense strand. A biantennary oligonucleotide compound of.
[Section 107] The SNP position nucleotide is complementary to an allelic polymorphism of the htt SNP selected from the group consisting of rs363125, rs362273, rs362307, rs362336, rs362331, rs362272, rs362306, rs362268, rs362267 and rs363099. A biantennary oligonucleotide compound according to .
Claims (49)
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、オリゴヌクレオチド。 an oligonucleotide having a 5′ end, a 3′ end and a seed region, which is complementary to the region of the gene containing the allelic polymorphism;
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and mismatching a nucleotide in said gene. , a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide.
必要に応じて、前記ＲＮＡは、式：
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項１に記載のＲＮＡ。 the oligonucleotide is RNA ,
Optionally, said RNA has the formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
The RNA of claim 1.
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、前記５’末端から２～６位における前記ＳＮＰ位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する前記ＭＭ位置ヌクレオチドを含み、
必要に応じて、前記ＳＮＰ位置ヌクレオチドは、前記第１の鎖の前記５’末端から２位、４位又は６位にあり、
必要に応じて、前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドの２、４又は６ヌクレオチド以内に位置し、
必要に応じて、前記ｄｓＲＮＡは、平滑末端であり、
必要に応じて、前記ｄｓＲＮＡは、少なくとも１つの一本鎖ヌクレオチドオーバーハングを含み、
必要に応じて、前記ｄｓＲＮＡは、天然に存在するヌクレオチドを含み、
必要に応じて、前記ｄｓＲＮＡは、少なくとも１つの修飾ヌクレオチドを含み、
必要に応じて、各ヌクレオチドは、修飾され、
必要に応じて、前記少なくとも１つの修飾ヌクレオチドは、２’－Ｏ－メチ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、コレステリル誘導体に連結された末端ヌクレオチド及びドデカン酸ビスデシルアミド基に連結された末端ヌクレオチドからなる群から選択され、
必要に応じて、前記修飾ヌクレオチドは、２’－デオキシ－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、脱塩基ヌクレオチド、２’－アミノ修飾ヌクレオチド、２’－アルキル修飾ヌクレオチド、モルホリノヌクレオチド、ホスホロアミダート及び非天然塩基を含むヌクレオチドからなる群から選択され、
必要に応じて、少なくとも１つの２’－Ｏ－メチル修飾ヌクレオチド及び５’－ホスホロチオエート基を含み、
必要に応じて、前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含み、
必要に応じて、前記第１の鎖は、前記ＳＮＰ位置ヌクレオチドのいずれかの側で２’－Ｏ－メチル修飾ヌクレオチドを含み、
必要に応じて、前記ｄｓＲＮＡは、疎水性部分を含み、
必要に応じて、前記アレル多型を含む遺伝子の前記領域は、配列番号１～１０からなる群から選択される核酸配列を含み、及び
必要に応じて、前記第１の鎖は、ＵＵＣＵＧＵＡＧＣＡＵＣＡＧＣＵＵＣＵＣを含む、
請求項４に記載のｄｓＲＮＡ。 a first strand of about 15-35 nucleotides complementary to said region of said gene containing the allelic polymorphism; and a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand. including
the first strand comprises the SNP position nucleotides at positions 2-6 from the 5' end that are complementary to the allelic polymorphism;
said first strand comprises said MM position nucleotide located 2-6 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene;
optionally, said SNP position nucleotide is at position 2, 4 or 6 from said 5' end of said first strand;
optionally, said MM position nucleotide is located within 2, 4 or 6 nucleotides of said SNP position nucleotide;
optionally, the dsRNA is blunt-ended;
optionally, said dsRNA comprises at least one single-stranded nucleotide overhang;
Optionally, said dsRNA comprises naturally occurring nucleotides,
optionally, said dsRNA comprises at least one modified nucleotide;
Optionally, each nucleotide is modified to
Optionally, said at least one modified nucleotide is linked to a 2′-O-methyl modified nucleotide, a nucleotide containing a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group. selected from the group consisting of terminal nucleotides,
Optionally, the modified nucleotides are 2'-deoxy-2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, locked nucleotides, abasic nucleotides, 2'-amino modified nucleotides, 2'-alkyl modified nucleotides. , morpholino nucleotides, phosphoramidates and nucleotides containing unnatural bases;
optionally comprising at least one 2'-O-methyl modified nucleotide and a 5'-phosphorothioate group;
optionally said first strand comprises at least three 2'-O-methyl modified nucleotides;
optionally, said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides;
Optionally, said dsRNA comprises a hydrophobic moiety,
Optionally, the region of the gene containing the allelic polymorphism comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-10, and
Optionally, said first strand comprises UUCUGUAGCAUCAGCCUUCUC
5. The dsRNA of claim 4 .
アレル多型を含む遺伝子の領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、５’末端から４位における一塩基多型（ＳＮＰ）位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記５’末端から７位に位置するミスマッチ（ＭＭ）位置ヌクレオチドを含む、二重鎖ＲＮＡ（ｄｓＲＮＡ）。 a double-stranded RNA (dsRNA),
a first strand of about 15-35 nucleotides complementary to the region of the gene containing the allelic polymorphism; and a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand;
the first strand comprises a single nucleotide polymorphism (SNP) position nucleotide at position 4 from the 5' end that is complementary to the allelic polymorphism;
A double-stranded RNA (dsRNA) wherein said first strand comprises a mismatch (MM) position nucleotide located at position 7 from said 5' end that is mismatched with a nucleotide in said gene.
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項６に記載のｄｓＲＮＡ。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
The dsRNA of claim 6 .
必要に応じて、前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含み、及び
必要に応じて、前記ｄｓＲＮＡは、５’－ホスホロチオエート基を含む、
請求項６に記載のｄｓＲＮＡ。 said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides;
optionally, said first strand comprises at least three 2'-O-methyl modified nucleotides, and
optionally, said dsRNA comprises a 5′-phosphorothioate group;
The dsRNA of claim 6 .
必要に応じて、前記第１の鎖は、ＵＵＣＵＧＵＡＧＣＡＵＣＡＧＣＵＵＣＵＣを含む、
請求項６に記載のｄｓＲＮＡ。 the region of the gene containing the allelic polymorphism comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1 to 10;
Optionally, said first strand comprises UUCUGUAGCAUCAGCCUUCUC
The dsRNA of claim 6 .
アレル多型を含む遺伝子の領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、５’末端から６位における一塩基多型（ＳＮＰ）位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記５’末端から１１位に位置するミスマッチ（ＭＭ）位置ヌクレオチドを含む、二重鎖ＲＮＡ（ｄｓＲＮＡ）。 a double-stranded RNA (dsRNA),
a first strand of about 15-35 nucleotides complementary to the region of the gene containing the allelic polymorphism; and a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand;
the first strand comprises a single nucleotide polymorphism (SNP) position nucleotide at position 6 from the 5' end that is complementary to the allelic polymorphism;
A double-stranded RNA (dsRNA) wherein said first strand comprises a mismatch (MM) position nucleotide located at position 11 from said 5' end that is mismatched with a nucleotide in said gene.
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項１１に記載のｄｓＲＮＡ。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
12. The dsRNA of claim 11 .
必要に応じて、前記第１の鎖は、少なくとも３つの２’－Ｏ－メチル修飾ヌクレオチドを含む、
請求項１１に記載のｄｓＲＮＡ。 said first strand comprises 2'-O-methyl modified nucleotides on either side of said SNP position nucleotides;
optionally, said first strand comprises at least three 2'-O-methyl modified nucleotides;
12. The dsRNA of claim 11 .
前記ＲＮＡは、
前記アレル多型と相補的である、前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、剤。 An agent for treating a disease or disorder characterized by or caused by a gene containing an allelic polymorphism in a subject in need thereof, the agent being complementary to the region of the gene containing the allelic polymorphism , an RNA having a 5′ end, a 3′ end and a seed region;
The RNA is
A single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region that is complementary to said allelic polymorphism; and a position 2-11 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene. comprising mismatched (MM) position nucleotides.
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項２０に記載の剤。 The RNA has the formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
The agent according to claim 20 .
アレル多型を含む前記遺伝子の前記領域と相補的な約１５～３５ヌクレオチドの第１の鎖；及び
前記第１の鎖の少なくとも一部と相補的な約１５～３５ヌクレオチドの第２の鎖
を含み、
前記第１の鎖は、前記アレル多型と相補的である、前記５’末端から２～６位における前記ＳＮＰ位置ヌクレオチドを含み、
前記第１の鎖は、前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する前記ＭＭ位置ヌクレオチドを含み、
必要に応じて、前記ｄｓＲＮＡは、前記対象の脳に投与され、
必要に応じて、前記ｄｓＲＮＡは、線条体内注入によって投与され、
必要に応じて、線条体における前記遺伝子の発現の減少は、達成され、
必要に応じて、前記皮質における前記遺伝子の発現の減少は、達成され、
必要に応じて、前記アレル多型を含む前記遺伝子は、ハンチンチン（ｈｔｔ）遺伝子であり、及び
必要に応じて、前記疾患は、ハンチントン病である、
請求項２１に記載の剤。 The dsRNA is
a first strand of about 15-35 nucleotides complementary to said region of said gene containing the allelic polymorphism; and a second strand of about 15-35 nucleotides complementary to at least a portion of said first strand. including
the first strand comprises the SNP position nucleotides at positions 2-6 from the 5' end that are complementary to the allelic polymorphism;
said first strand comprises said MM position nucleotide located 2-6 nucleotides from said SNP position nucleotide that is mismatched with a nucleotide in said gene;
optionally, the dsRNA is administered to the subject's brain,
optionally, the dsRNA is administered by intrastriatal injection;
optionally reducing expression of said gene in the striatum is achieved,
optionally reducing expression of said gene in said cortex is achieved,
Optionally, said gene comprising said allelic polymorphism is a huntingtin (htt) gene, and
Optionally, said disease is Huntington's disease.
The agent according to claim 21 .
必要に応じて、前記ＳＮＰ位置ヌクレオチドは、ｒｓ３６３１２５、ｒｓ３６２２７３、ｒｓ３６２３０７、ｒｓ３６２３３６、ｒｓ３６２３３１、ｒｓ３６２２７２、ｒｓ３６２３０６、ｒｓ３６２２６８、ｒｓ３６２２６７及びｒｓ３６３０９９からなる群から選択されるｈｔｔ ＳＮＰのアレル多型と相補的であり、
必要に応じて、ホスフェート、ビニルホスホネート、Ｃ５－メチル（Ｒ、又はＳ、又はラセミ）、ビニル上のＣ５－メチル及び還元ビニルからなる群から選択される５’安定化部分をさらに含み、及び
必要に応じて、アルキル鎖、ビタミン、ペプチド、スフィンゴ糖脂質、多価不飽和脂肪酸、セコステロイド、ステロイドホルモン及びステロイド脂質からなる群から選択されるコンジュゲート部分をさらに含む、
請求項１に記載のＲＮＡ。 the SNP position nucleotide is located 2, 4 or 6 from the 5' end of the RNA, and the MM position nucleotide is located 2-6 nucleotides from the SNP position nucleotide;
optionally, said SNP position nucleotide is complementary to an allelic polymorphism of the htt SNP selected from the group consisting of rs363125, rs362273, rs362307, rs362336, rs362331, rs362272, rs362306, rs362268, rs362267 and rs363099;
optionally further comprising a 5′ stabilizing moiety selected from the group consisting of phosphate, vinyl phosphonate, C5-methyl (R, or S, or racemic), C5-methyl on vinyl and reduced vinyl; and
optionally further comprising a conjugate moiety selected from the group consisting of alkyl chains, vitamins, peptides, glycosphingolipids, polyunsaturated fatty acids, secosteroids, steroid hormones and steroid lipids;
The RNA of claim 1.
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、二分岐オリゴヌクレオチド化合物。 A biantennary oligonucleotide compound comprising two RNAs, said RNAs linked together by one or more moieties selected from linkers, spacers and branch points, each RNA having a 5′ end, a 3′ end and a having a seed region, each RNA being complementary to a region of the gene containing the allelic polymorphism, each RNA comprising:
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and mismatching a nucleotide in said gene. , a biantennary oligonucleotide compound comprising a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide.
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項２５に記載の二分岐オリゴヌクレオチド化合物。 The RNA has the formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
26. The biantennary oligonucleotide compound of claim 25 .
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）
を含む、核酸。 A nucleic acid having a 5′ end, a 3′ end and a seed region complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X being 4 from said SNP position nucleotide; at least one modified nucleotide (X) located within 3 or 2 nucleotides
Nucleic acids, including
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項２９に記載の核酸。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
30. A nucleic acid according to claim 29 .
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）
を含む、核酸。 A nucleic acid having a 5′ end, a 3′ end and a seed region complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X being 4 from said SNP position nucleotide; at least one modified nucleotide (X) located within 3 or 2 nucleotides
Nucleic acids, including
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項３１に記載の核酸。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
32. The nucleic acid of claim 31 .
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＭＭ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｙ）であって、各Ｙは、前記ＭＭ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｙ）
を含む、核酸。 A nucleic acid having a 5′ end, a 3′ end and a seed region complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and at least one modified nucleotide (Y) on either side of said MM position nucleotide, each Y being 4 from said MM position nucleotide; at least one modified nucleotide (Y) located within 3 or 2 nucleotides
Nucleic acids, including
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項３３に記載の核酸。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
34. The nucleic acid of claim 33 .
必要に応じて、前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～１１又は２～６ヌクレオチドに位置する、
請求項３１又は３３に記載の核酸。 The SNP position nucleotide is present at positions 2 to 6 from the 5' end,
Optionally, said MM position nucleotide is located 2-11 or 2-6 nucleotides from said SNP position nucleotide,
34. A nucleic acid according to claim 31 or 33 .
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；
前記遺伝子中のヌクレオチドとミスマッチであるミスマッチ（ＭＭ）位置；及び
前記ＳＮＰ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｘ）であって、各Ｘは、前記ＳＮＰ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｘ）；及び
前記ＭＭ位置ヌクレオチドのいずれかの側での少なくとも１つの修飾ヌクレオチド（Ｙ）であって、各Ｙは、前記ＭＭ位置ヌクレオチドから４、３又は２ヌクレオチド以内に位置する、少なくとも１つの修飾ヌクレオチド（Ｙ）
を含む、核酸。 A nucleic acid having a 5′ end, a 3′ end and a seed region complementary to a region of a gene containing an allelic polymorphism,
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism;
a mismatch (MM) position that is mismatched with a nucleotide in said gene; and at least one modified nucleotide (X) on either side of said SNP position nucleotide, each X being 4 from said SNP position nucleotide; at least one modified nucleotide (X) located within 3 or 2 nucleotides; and at least one modified nucleotide (Y) on either side of said MM position nucleotide, each Y being said MM position nucleotide at least one modified nucleotide (Y) located within 4, 3 or 2 nucleotides from
Nucleic acids, including
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項４２に記載の核酸。 formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
43. The nucleic acid of claim 42 .
必要に応じて、前記Ｙは、２’－ＯＭｅ、２’－Ｆ、２’－リボ、２’－デオキシリボ、２’－Ｆ－ＡＮＡ、２’－ＭＯＥ、４’－Ｓ－ＲＮＡ、ＬＮＡ、４’－Ｓ－Ｆ－ＡＮＡ、２’－Ｏ－アリル、２’－Ｏ－エチルアミン、ＣＮｅｔ－ＲＮＡ、トリシクロ－ＤＮＡ、ＣｅＮＡ、ＡＮＡ及びＨＮＡからなる群から選択される糖修飾を含み、
必要に応じて、前記Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近又は前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置し、
必要に応じて、前記Ｘは、前記ＳＮＰ位置ヌクレオチドに対する５’の直近及び前記ＳＮＰ位置ヌクレオチドに対する３’の直近に位置し、
必要に応じて、前記Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近又は前記ＭＭ位置ヌクレオチドに対する３’の直近に位置し、
必要に応じて、前記Ｙは、前記ＭＭ位置ヌクレオチドに対する５’の直近及び前記ＭＭ位置ヌクレオチドに対する３’の直近に位置し、
必要に応じて、前記ＳＮＰ位置ヌクレオチドは、前記５’末端から２位～６位に存在し、
必要に応じて、前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置し、及び
必要に応じて、前記ＭＭ位置ヌクレオチドは、前記ＳＮＰ位置ヌクレオチドから２～６ヌクレオチドに位置する、
請求項４２に記載の核酸。 X is 2′-OMe, 2′-F, 2′-ribo, 2′-deoxyribo, 2′-F-ANA, 2′-MOE, 4′-S-RNA, LNA, 4′-SF - a sugar modification selected from the group consisting of ANA, 2'-O-allyl, 2'-O-ethylamine, CNet-RNA, tricyclo-DNA, CeNA , ANA and HNA;
Optionally, Y is 2′-OMe, 2′-F, 2′-ribo, 2′-deoxyribo, 2′-F-ANA, 2′-MOE, 4′-S-RNA, LNA, a sugar modification selected from the group consisting of 4'-SF-ANA, 2'-O-allyl, 2'-O-ethylamine, CNet-RNA, tricyclo-DNA, CeNA, ANA and HNA;
optionally, said X is located immediately 5′ to said SNP position nucleotide or immediately 3′ to said SNP position nucleotide;
optionally, said X is positioned immediately 5′ to said SNP position nucleotide and immediately 3′ to said SNP position nucleotide;
optionally, said Y is located immediately 5′ to said MM position nucleotide or immediately 3′ to said MM position nucleotide;
optionally, said Y is positioned immediately 5′ to said nucleotide at the MM position and immediately 3′ to said nucleotide at the MM position;
optionally, the SNP position nucleotides are present at positions 2 to 6 from the 5'end;
Optionally, said MM position nucleotide is located 2-11 nucleotides from said SNP position nucleotide, and
optionally, said MM position nucleotide is located 2-6 nucleotides from said SNP position nucleotide;
43. The nucleic acid of claim 42 .
各核酸配列は、二重鎖であり、且つセンス鎖及びアンチセンス鎖を含み、前記センス鎖及び前記アンチセンス鎖は、それぞれ５’末端及び３’末端を有し、前記センス鎖及び前記アンチセンス鎖は、それぞれ１つ以上の化学修飾されたヌクレオチドを含み、
各アンチセンス鎖は、シード領域を有し、各アンチセンス鎖は、アレル多型を含む遺伝子の領域と相補的であり、各アンチセンス鎖は、
前記シード領域内の位置での一塩基多型（ＳＮＰ）位置ヌクレオチドであって、前記アレル多型と相補的である一塩基多型（ＳＮＰ）位置ヌクレオチド；及び
前記遺伝子中のヌクレオチドとミスマッチである、前記ＳＮＰ位置ヌクレオチドから２～１１ヌクレオチドに位置するミスマッチ（ＭＭ）位置ヌクレオチド
を含む、二分岐オリゴヌクレオチド化合物。 A biantennary oligonucleotide compound comprising two or more nucleic acid sequences, wherein said nucleic acid sequences (N) are one selected from linkers (L), spacers (S) and optionally branch points (B) connected to each other by the above parts,
Each nucleic acid sequence is double-stranded and comprises a sense strand and an antisense strand, said sense strand and said antisense strand having 5′ and 3′ ends, respectively, said sense strand and said antisense strand the strands each comprise one or more chemically modified nucleotides,
Each antisense strand has a seed region, each antisense strand is complementary to a region of the gene containing the allelic polymorphism, and each antisense strand comprises
a single nucleotide polymorphism (SNP) position nucleotide at a position within said seed region, said single nucleotide polymorphism (SNP) position nucleotide being complementary to said allelic polymorphism; and mismatching a nucleotide in said gene. , a biantennary oligonucleotide compound comprising a mismatch (MM) position nucleotide located 2-11 nucleotides from said SNP position nucleotide.
必要に応じて、前記ＶＰモチーフは、前記ＳＮＰ位置ヌクレオチドの隣又は前記ＭＭ位置ヌクレオチドの隣に挿入される、
請求項４７に記載の二分岐オリゴヌクレオチド化合物。 The RNA has the formula:
optionally, said VP motif is inserted next to said SNP position nucleotide or next to said MM position nucleotide;
48. The biantennary oligonucleotide compound of claim 47 .
必要に応じて、前記センス及びアンチセンス鎖の前記５’末端から１及び２位での前記ヌクレオチドは、ホスホロチオエート結合を介して隣接ヌクレオチドに連結され、
必要に応じて、各アンチセンス鎖は、少なくとも１５個の連続したヌクレオチドを含み、各センス鎖は、少なくとも１５個の連続したヌクレオチドを含み、且つ前記アンチセンス鎖に対して相補性を有し、
必要に応じて、前記分岐オリゴヌクレオチド化合物の末端５’位に結合された疎水性部分をさらに含み、
必要に応じて、各二重鎖核酸配列は、前記センス鎖又は前記アンチセンス鎖の前記３’末端又は前記５’末端でのリンカー、スペーサー又は分岐点に独立して連結され、及び
必要に応じて、前記ＳＮＰ位置ヌクレオチドは、ｒｓ３６３１２５、ｒｓ３６２２７３、ｒｓ３６２３０７、ｒｓ３６２３３６、ｒｓ３６２３３１、ｒｓ３６２２７２、ｒｓ３６２３０６、ｒｓ３６２２６８、ｒｓ３６２２６７及びｒｓ３６３０９９からなる群から選択されるｈｔｔ ＳＮＰのアレル多型と相補的である、
請求項４７に記載の二分岐オリゴヌクレオチド化合物。 the sense strand and the antisense strand each comprise >80% chemically modified nucleotides;
optionally, the nucleotides at positions 1 and 2 from the 5' ends of the sense and antisense strands are linked to adjacent nucleotides via phosphorothioate linkages;
optionally each antisense strand comprises at least 15 contiguous nucleotides and each sense strand comprises at least 15 contiguous nucleotides and is complementary to said antisense strand;
optionally further comprising a hydrophobic moiety attached to the terminal 5' position of said branched oligonucleotide compound;
optionally, each double-stranded nucleic acid sequence is independently linked to a linker, spacer or branch point at the 3′ end or the 5′ end of the sense strand or the antisense strand; and
optionally, said SNP position nucleotide is complementary to an allelic polymorphism of the htt SNP selected from the group consisting of rs363125, rs362273, rs362307, rs362336, rs362331, rs362272, rs362306, rs362268, rs362267 and rs363099;
48. The biantennary oligonucleotide compound of claim 47 .
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| EP3833763A4 (en) | 2018-08-10 | 2023-07-19 | University of Massachusetts | Modified oligonucleotides targeting snps |
| JP2022523467A (en) | 2019-01-18 | 2022-04-25 | ユニバーシティ・オブ・マサチューセッツ | Anchors that modify dynamic pharmacokinetics |
-
2019
- 2019-08-09 EP EP19847586.5A patent/EP3833763A4/en active Pending
- 2019-08-09 BR BR112021002440-9A patent/BR112021002440A2/en unknown
- 2019-08-09 SG SG11202101288TA patent/SG11202101288TA/en unknown
- 2019-08-09 CA CA3109133A patent/CA3109133A1/en active Pending
- 2019-08-09 JP JP2021507003A patent/JP2021533762A/en active Pending
- 2019-08-09 MX MX2021001590A patent/MX2021001590A/en unknown
- 2019-08-09 US US16/537,374 patent/US11827882B2/en active Active
- 2019-08-09 KR KR1020217006987A patent/KR20210093227A/en unknown
- 2019-08-09 CN CN201980066120.2A patent/CN112805383A/en active Pending
- 2019-08-09 WO PCT/US2019/046013 patent/WO2020033899A1/en active Search and Examination
- 2019-08-09 AU AU2019316640A patent/AU2019316640A1/en active Pending
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2021
- 2021-02-08 IL IL280724A patent/IL280724A/en unknown
-
2023
- 2023-08-09 US US18/446,929 patent/US20240132888A1/en active Pending
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