JPWO2021216556A5

JPWO2021216556A5 -

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Publication number: JPWO2021216556A5
Application number: JP2022563451A
Authority: JP
Publication date: 2024-05-02

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均等物
本開示は、その精神または本質的特徴から逸脱することなく、他の特定の形態で具現化され得る。したがって、前述の実施形態は、本開示を限定するものではなく、あらゆる点において例示的であると見なされるべきである。したがって、本開示の範囲は、前述の説明によってではなく添付の特許請求の範囲によって示され、特許請求の範囲の意味及び均等の範囲内に入るすべての変更は、本明細書に含まれることが意図される。
本発明の態様には、以下が含まれる。
［項１］センス鎖及びアンチセンス鎖を含む二本鎖ＲＮＡ（ｄｓＲＮＡ）分子であって、
前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む、前記分子。
［項２］前記アンチセンス鎖が、配列番号１３～１８及び３１～４２のいずれか１つに記載のＭＳＨ３核酸配列に実質的に相補的な配列を含む、項１に記載のｄｓＲＮＡ。
［項３］配列番号１～６及び１９～３０のいずれか１つの前記ＭＳＨ３核酸配列の少なくとも１０、１１、１２、または１３の連続ヌクレオチドに対する相補性を含む、項１に記載のｄｓＲＮＡ。
［項４］配列番号１～６及び１９～３０のいずれか１つの前記ＭＳＨ３核酸配列との３つ以下のミスマッチを含む、項１または３に記載のｄｓＲＮＡ。
［項５］配列番号１～６及び１９～３０のいずれか１つの前記ＭＳＨ３核酸配列に対する完全な相補性を含む、項１に記載のｄｓＲＮＡ。
［項６］前記アンチセンス鎖が、約１５ヌクレオチド～２５ヌクレオチド長を含む、項１～５のいずれか一項に記載のｄｓＲＮＡ。
［項７］前記センス鎖が、約１５ヌクレオチド長～２５ヌクレオチド長を含む、項１～６のいずれか一項に記載のｄｓＲＮＡ。
［項８］前記アンチセンス鎖が、２０ヌクレオチド長である、項１～７のいずれか一項に記載のｄｓＲＮＡ。
［項９］前記アンチセンス鎖が、２１ヌクレオチド長である、項１～７のいずれか一項に記載のｄｓＲＮＡ。
［項１０］前記アンチセンス鎖が、２２ヌクレオチド長である、項１～７のいずれか一項に記載のｄｓＲＮＡ。
［項１１］前記センス鎖が、１５ヌクレオチド長である、項１～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１２］前記センス鎖が、１６ヌクレオチド長である、項１～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１３］前記センス鎖が、１８ヌクレオチド長である、項１～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１４］前記センス鎖が、２０ヌクレオチド長である、項１～１０のいずれか一項に記載のｄｓＲＮＡ。
［項１５］１５塩基対～２０塩基対の二本鎖領域を含む、項１～１４のいずれか一項に記載のｄｓＲＮＡ。
［項１６］１５塩基対の二本鎖領域を含む、項１～１５のいずれか一項に記載のｄｓＲＮＡ。
［項１７］１６塩基対の二本鎖領域を含む、項１～１５のいずれか一項に記載のｄｓＲＮＡ。
［項１８］１８塩基対の二本鎖領域を含む、項１～１５のいずれか一項に記載のｄｓＲＮＡ。
［項１９］２０塩基対の二本鎖領域を含む、項１～１５のいずれか一項に記載のｄｓＲＮＡ。
［項２０］前記ｄｓＲＮＡが、平滑末端を含む、項１～１９のいずれか一項に記載のｄｓＲＮＡ。
［項２１］前記ｄｓＲＮＡが、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１～２０のいずれか一項に記載のｄｓＲＮＡ。
［項２２］前記ｄｓＲＮＡが、約２ヌクレオチド～５ヌクレオチドの一本鎖ヌクレオチドオーバーハングを含む、項２１に記載のｄｓＲＮＡ。
［項２３］前記ｄｓＲＮＡが、２ヌクレオチドの一本鎖ヌクレオチドオーバーハングを含む、項２１に記載のｄｓＲＮＡ。
［項２４］前記ｄｓＲＮＡが、５ヌクレオチドの一本鎖ヌクレオチドオーバーハングを含む、項２１に記載のｄｓＲＮＡ。
［項２５］前記ｄｓＲＮＡが、天然に存在するヌクレオチドを含む、項１～２４のいずれか一項に記載のｄｓＲＮＡ。
［項２６］前記ｄｓＲＮＡが、少なくとも１つの修飾ヌクレオチドを含む、項１～２４のいずれか一項に記載のｄｓＲＮＡ。
［項２７］前記修飾ヌクレオチドが、２’－Ｏ－メチル修飾ヌクレオチド、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、ホスホルアミデート、ヌクレオチドを含む非天然塩基、またはそれらの混合物を含む、項２６に記載のｄｓＲＮＡ。
［項２８］前記ｄｓＲＮＡが、少なくとも１つの修飾ヌクレオチド間連結を含む、項１～２７のいずれか一項に記載のｄｓＲＮＡ。
［項２９］前記修飾ヌクレオチド間連結が、ホスホロチオエートヌクレオチド間連結を含む、項２８に記載のｄｓＲＮＡ。
［項３０］４～１６のホスホロチオエートヌクレオチド間連結を含む、項１～２９のいずれか一項に記載のｄｓＲＮＡ。
［項３１］８～１３のホスホロチオエートヌクレオチド間連結を含む、項１～２９のいずれか一項に記載のｄｓＲＮＡ。
［項３２］前記ｄｓＲＮＡが、式Ｉの少なくとも１つの修飾ヌクレオチド間連結を含む、項１～２８のいずれか一項に記載のｄｓＲＮＡ：

（式中、
Ｂは、塩基対部分であり；
Ｗは、Ｏ、ＯＣＨ _２、ＯＣＨ、ＣＨ _２、及びＣＨからなる群から選択され；
Ｘは、ハロ、ヒドロキシ、及びＣ _１－６アルコキシからなる群から選択され、
Ｙは、Ｏ ^－、ＯＨ、ＯＲ、ＮＨ ^－、ＮＨ _２、Ｓ ^－、及びＳＨからなる群から選択され、
Ｚは、Ｏ及びＣＨ _２からなる群から選択され；
Ｒは、保護基であり、

は、任意の二重結合である）。
［項３３］前記ｄｓＲＮＡが、少なくとも８０％の化学修飾ヌクレオチドを含む、項１～３２のいずれか一項に記載のｄｓＲＮＡ。
［項３４］前記ｄｓＲＮＡが、完全化学修飾されている、項１～３３のいずれか一項に記載のｄｓＲＮＡ。
［項３５］前記ｄｓＲＮＡが、少なくとも７０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項１～３３のいずれか一項に記載のｄｓＲＮＡ。
［項３６］前記アンチセンス鎖が、少なくとも７０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項１～３３のいずれか一項に記載のｄｓＲＮＡ。
［項３７］前記アンチセンス鎖が、７０％～９０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項３６に記載のｄｓＲＮＡ。
［項３８］前記センス鎖が、少なくとも６５％の２’－Ｏ－メチルヌクレオチド修飾を含む、項１～３３のいずれか一項に記載のｄｓＲＮＡ。
［項３９］前記センス鎖が、１００％の２’－Ｏ－メチルヌクレオチド修飾を含む、項３８に記載のｄｓＲＮＡ。
［項４０］前記センス鎖が、前記アンチセンス鎖と前記センス鎖との間に１つ以上のヌクレオチドミスマッチを含む、項１～３９のいずれか一項に記載のｄｓＲＮＡ。
［項４１］前記１つ以上のヌクレオチドミスマッチが、センス鎖の５’末端から２位、６位、及び１２位に存在する、項４０に記載のｄｓＲＮＡ。
［項４２］前記のヌクレオチドミスマッチが、前記センス鎖の５’末端から２位、６位、及び１２位に存在する、項４０に記載のｄｓＲＮＡ。
［項４３］前記アンチセンス鎖が、５’リン酸、５’－アルキルホスホネート、５’アルキレンホスホネート、または５’アルケニルホスホネートを含む、項１～４２のいずれか一項に記載のｄｓＲＮＡ。
［項４４］前記アンチセンス鎖が、５’ビニルホスホネートを含む、項４３に記載のｄｓＲＮＡ。
［項４５］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、２’－メトキシ－リボヌクレオチド及び２’－フルオロ－リボヌクレオチドを交互に含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、２’－メトキシ－リボヌクレオチド及び２’－フルオロ－リボヌクレオチドを交互に含む；
（７）前記センス鎖の５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項４６］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７０％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも７０％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項４７］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも８５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項４８］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から４位、５位、６位、及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項４９］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位、４位、５位、６位、及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項５０］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位、６位、１４位、及び１６位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも６５％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記３’末端から７位、９位、１０位、及び１１位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（８）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項５１］アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有する、項１に記載のｄｓＲＮＡであって、
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記３’末端から７位、１０位、及び１１位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（８）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、前記ｄｓＲＮＡ。
［項５２］機能部分が、前記アンチセンス鎖の前記５’末端及び／または３’末端に連結されている、項１～５１のいずれか一項に記載のｄｓＲＮＡ。
［項５３］機能部分が、前記センス鎖の前記５’末端及び／または３’末端に連結されている、項１～５１のいずれか一項に記載のｄｓＲＮＡ。
［項５４］機能部分が、前記センス鎖の前記３’末端に連結されている、項１～５１のいずれか一項に記載のｄｓＲＮＡ。
［項５５］前記機能部分が、疎水性部分を含む、項５２～５４のいずれか一項に記載のｄｓＲＮＡ。
［項５６］前記疎水性部分が、脂肪酸、ステロイド、セコステロイド、脂質、ガングリオシド、ヌクレオシド類似体、エンドカンナビノイド、ビタミン、及びそれらの混合物からなる群から選択される、項５５に記載のｄｓＲＮＡ。
［項５７］前記ステロイドが、コレステロール及びリトコール酸（ＬＣＡ）からなる群から選択される、項５６に記載のｄｓＲＮＡ。
［項５８］前記脂肪酸が、エイコサペンタエン酸（ＥＰＡ）、ドコサヘキサエン酸（ＤＨＡ）、及びドコサン酸（ＤＣＡ）からなる群から選択される、項５６に記載のｄｓＲＮＡ。
［項５９］前記ビタミンが、コリン、ビタミンＡ、ビタミンＥ、及び誘導体、またはそれらの代謝物からなる群から選択される、項５６に記載のｄｓＲＮＡ。
［項６０］前記ビタミンが、レチノイン酸及びコハク酸アルファ－トコフェロールからなる群から選択される、項５９に記載のｄｓＲＮＡ。
［項６１］前記機能部分が、リンカーにより前記アンチセンス鎖及び／またはセンス鎖に連結されている、項５４～６０のいずれか一項に記載のｄｓＲＮＡ。
［項６２］前記リンカーが、二価または三価のリンカーを含む、項６１に記載のｄｓＲＮＡ。
［項６３］前記二価または三価のリンカーが、

（式中、ｎは、１、２、３、４、または５である）から選択される、項６２に記載のｄｓＲＮＡ。
［項６４］前記リンカーが、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスホジエステル、ホスホロチオエート、ホスホルアミデート、アミド、カルバメート、またはそれらの組み合わせを含む、項６１または６２に記載のｄｓＲＮＡ。
［項６５］前記リンカーが、三価リンカーである場合、前記リンカーは、ホスホジエステルまたはホスホジエステル誘導体をさらに連結する、項６２または６３に記載のｄｓＲＮＡ。
［項６６］前記ホスホジエステルまたはホスホジエステル誘導体が、以下からなる群から選択される、項６５に記載のｄｓＲＮＡ：

（式中、Ｘは、Ｏ、ＳまたはＢＨ _３である）。
［項６７］センス鎖の前記３’末端から１位及び２位の前記ヌクレオチド、及びアンチセンス鎖の前記５’末端から１位及び２位の前記ヌクレオチドが、ホスホロチオエート結合を介して隣接するリボヌクレオチドに結合される、項１～６６のいずれか一項に記載のｄｓＲＮＡ。
［項６８］項１～６７のいずれか一項に記載のｄｓＲＮＡ及び薬学的に許容される担体を含む、生物におけるＭＳＨ３遺伝子の発現を阻害するための医薬組成物。
［項６９］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも５０％阻害する、項６８に記載の医薬組成物。
［項７０］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも８０％阻害する、項６８に記載の医薬組成物。
［項７１］細胞におけるＭＳＨ３遺伝子の発現を調節するための方法であって、
（ａ）項１～６７のいずれか一項に記載の二本鎖リボ核酸（ｄｓＲＮＡ）を前記細胞に導入するステップと；
（ｂ）ステップ（ａ）で産生された前記細胞を、前記ＭＳＨ３遺伝子の前記ｍＲＮＡ転写物の分解を得るのに十分な時間維持し、それによって前記細胞中の前記ＭＳＨ３遺伝子の発現を阻害することと、を含む、前記方法。
［項７２］神経変性疾患を治療または管理する方法であって、こうした治療を必要とする患者に、治療有効量の項１～６７のいずれか一項に記載のｄｓＲＮＡを投与することを含む、前記方法。
［項７３］前記ｄｓＲＮＡが、前記患者の脳に投与される、項７２に記載の方法。
［項７４］前記ｄｓＲＮＡが、脳・脳室内（ＩＣＶ）注射、線条体内（ＩＳ）注射、静脈内（ＩＶ）注射、皮下（ＳＱ）注射、またはそれらの組み合わせによって投与される、項７２に記載の方法。
［項７５］前記ｄｓＲＮＡを投与することは、海馬、線条体、皮質、小脳、視床、視床下部、及び脊髄のうちの１つ以上において、ＭＳＨ３遺伝子ｍＲＮＡの減少を引き起こす、項７２に記載の方法。
［項７６］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも５０％阻害する、項７１～７５のいずれか一項に記載の方法。
［項７７］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも８０％阻害する、項７１～７５のいずれか一項に記載の方法。
［項７８］配列番号１～６及び１９～３０のＭＳＨ３核酸配列に実質的に相補的なｄｓＲＮＡ分子をコードするヌクレオチド配列に作動可能に連結された調節配列を含むベクター。
［項７９］前記ＲＮＡ分子が、前記ＭＳＨ３遺伝子の前記発現を少なくとも３０％阻害する、項７８に記載のベクター。
［項８０］前記ＲＮＡ分子が、前記ＭＳＨ３遺伝子の前記発現を少なくとも５０％阻害する、項７８に記載のベクター。
［項８１］前記ＲＮＡ分子が、前記ＭＳＨ３遺伝子の前記発現を少なくとも８０％阻害する、項７８に記載のベクター。
［項８２］前記ｄｓＲＮＡが、センス鎖及びアンチセンス鎖を含み、前記アンチセンス鎖が、配列番号１～６及び１９～３０のＭＳＨ３核酸配列に実質的に相補的な配列を含む、項７８に記載のベクター。
［項８３］項７８～８２のいずれか一項に記載のベクターを含む細胞。
［項８４］項７８～８２のいずれか一項に記載のベクター及びＡＡＶキャプシドを含む、組換えアデノ随伴ウイルス（ｒＡＡＶ）。
［項８５］互いに共有結合により結合されている項１～６７のいずれか一項に記載のｄｓＲＮＡ分子の２つ以上を含む、分岐ＲＮＡ化合物。
［項８６］前記ｄｓＲＮＡ分子が、リンカー、スペーサー、または分岐点によって互いに共有結合により結合している、項８５に記載の分岐ＲＮＡ化合物。
［項８７］１５～３５ヌクレオチド長を含む２つ以上のＲＮＡ分子、及び
ＭＳＨ３ｍＲＮＡに実質的に相補的な配列を含み、
前記２つのＲＮＡ分子が、リンカー、スペーサー及び分岐点から独立して選択される１つ以上の部分によって互いに結合される、分岐ＲＮＡ化合物。
［項８８］配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む、項８７に記載の分岐ＲＮＡ化合物。
［項８９］配列番号１３～１８及び３１～４２のいずれか１つのＭＳＨ３核酸配列の１つ以上に実質的に相補的な核酸配列を含む、項８７に記載の分岐ＲＮＡ化合物。
［項９０］前記ＲＮＡ分子が、ｓｓＲＮＡ及びｄｓＲＮＡの一方または両方を含む、項８７～８９のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９１］前記ＲＮＡ分子が、アンチセンスオリゴヌクレオチドを含む、項８７～９０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９２］各ＲＮＡ分子が、１５～２５ヌクレオチド長を含む、項８７～９１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９３］各ＲＮＡ分子が、センス鎖及びアンチセンス鎖を含むｄｓＲＮＡを含み、各アンチセンス鎖が、独立して、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む、項８７～９０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９４］配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列の少なくとも１０、１１、１２、または１３の連続ヌクレオチドに対する相補性を含む、項９３に記載の分岐ＲＮＡ化合物。
［項９５］各ＲＮＡ分子が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列との３つ以下のミスマッチを含む、項９３に記載の分岐ＲＮＡ化合物。
［項９６］配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に対して完全な相補性を含む、項９３に記載の分岐ＲＮＡ化合物。
［項９７］前記アンチセンス鎖が、配列番号７～１２のいずれか１つの前記核酸配列を有する部分を含む、項９３～９６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９８］前記アンチセンス鎖及び／または前記センス鎖が、約１５ヌクレオチド～２５ヌクレオチド長を含む、項９３～９７のいずれか一項に記載の分岐ＲＮＡ化合物。
［項９９］前記アンチセンス鎖が、２０ヌクレオチド長である、項９３～９８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１００］前記アンチセンス鎖が、２１ヌクレオチド長である、項９３～９８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０１］前記アンチセンス鎖が、２２ヌクレオチド長である、項９３～９８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０２］前記センス鎖が、１５ヌクレオチド長である、項９３～１０１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０３］前記センス鎖が、１６ヌクレオチド長である、項９３～１０１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０４］前記センス鎖が、１８ヌクレオチド長である、項９３～１０１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０５］前記センス鎖が、２０ヌクレオチド長である、項９３～１０１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０６］前記ｄｓＲＮＡが、１５塩基対～２０塩基対の二本鎖領域を含む、項９０～１０５のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０７］前記ｄｓＲＮＡが、１５塩基対の二本鎖領域を含む、項９０～１０６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０８］前記ｄｓＲＮＡが、１６塩基対の二本鎖領域を含む、項９０～１０６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１０９］前記ｄｓＲＮＡが、１８塩基対の二本鎖領域を含む、項９０～１０６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１０］前記ｄｓＲＮＡが、２０塩基対の二本鎖領域を含む、項９０～１０６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１１］前記ｄｓＲＮＡが、平滑末端を含む、項９０～１１０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１２］前記ｄｓＲＮＡが、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９０～１１０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１３］前記ｄｓＲＮＡが、２ヌクレオチド～５ヌクレオチドの一本鎖ヌクレオチドオーバーハングを含む、項９０～１１２のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１４］前記ｄｓＲＮＡが、天然に存在するヌクレオチドを含む、項９０～１１３のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１５］前記ｄｓＲＮＡが、少なくとも１つの修飾ヌクレオチドを含む、項９０～１１４のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１６］前記修飾ヌクレオチドが、２’－Ｏ－メチル修飾ヌクレオチド、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、ホスホルアミデート、またはヌクレオチドを含む非天然塩基を含む、項１１５に記載の分岐ＲＮＡ化合物。
［項１１７］前記ｄｓＲＮＡが、少なくとも１つの修飾ヌクレオチド間連結を含む、項９０～１１６のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１１８］前記修飾ヌクレオチド間連結が、ホスホロチオエートヌクレオチド間連結を含む、項１１７に記載の分岐ＲＮＡ化合物。
［項１１９］４～１６のホスホロチオエートヌクレオチド間連結を含む、項９０～１１８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２０］８～１３のホスホロチオエートヌクレオチド間連結を含む、項９０～１１８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２１］前記ｄｓＲＮＡが、式（Ｉ）の少なくとも１つの修飾ヌクレオチド間連結を含む、項９０～１１７のいずれか一項に記載の分岐ＲＮＡ化合物：

は、任意の二重結合である）。
［項１２２］前記ｄｓＲＮＡが、少なくとも８０％の化学修飾ヌクレオチドを含む、項９０～１２１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２３］前記ｄｓＲＮＡが、完全に化学修飾されている、項９０～１２１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２４］前記ｄｓＲＮＡが、少なくとも７０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項９０～１２１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２５］前記アンチセンス鎖が、少なくとも７０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項９０～１２４のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２６］前記アンチセンス鎖が、７０％～９０％の２’－Ｏ－メチルヌクレオチド修飾を含む、項１２５に記載の分岐ＲＮＡ化合物。
［項１２７］前記センス鎖が、少なくとも６５％の２’－Ｏ－メチルヌクレオチド修飾を含む、項９０～１２４のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１２８］前記センス鎖が、１００％の２’－Ｏ－メチルヌクレオチド修飾を含む、項１２７に記載の分岐ＲＮＡ化合物。
［項１２９］前記センス鎖が、前記アンチセンス鎖と前記センス鎖との間に１つ以上のヌクレオチドミスマッチを含む、項９３～１２８のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１３０］前記１つ以上のヌクレオチドミスマッチが、センス鎖の前記５’末端から２位、６位、及び１２位に存在する、項１２９に記載の分岐ＲＮＡ化合物。
［項１３１］前記ヌクレオチドミスマッチが、前記センス鎖の５’末端から２位、６位、及び１２位に存在する、項１２９に記載の分岐ＲＮＡ化合物。
［項１３２］前記アンチセンス鎖が、５’リン酸、５’－アルキルホスホネート、５’アルキレンホスホネート、５’アルケニルホスホネート、またはそれらの混合物を含む、項９３～１３１のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１３３］前記アンチセンス鎖が、５’ビニルホスホネートを含む、項１３２に記載の分岐ＲＮＡ化合物。
［項１３４］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、２’－メトキシ－リボヌクレオチド及び２’－フルオロ－リボヌクレオチドを交互に含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、２’－メトキシ－リボヌクレオチド及び２’－フルオロ－リボヌクレオチドを交互に含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１３５］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７０％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも７０％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１３６］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも８５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１３７］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から４位、５位、６位、及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１３８］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位、４位、５位、６位、及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、１００％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１３９］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位、６位、１４位、及び１６位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも６５％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記３’末端から７位、９位、１０位、及び１１位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（８）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１４０］前記ｄｓＲＮＡが、アンチセンス鎖及びセンス鎖を含み、各鎖が５’末端及び３’末端を有し、ここで：
（１）前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含む；
（２）前記アンチセンス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（３）前記アンチセンス鎖の前記５’末端から２位及び１４位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（４）前記アンチセンス鎖の前記３’末端から１～２位から１～７位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している；
（５）前記アンチセンス鎖の一部が、前記センス鎖の一部に相補的である；
（６）前記センス鎖が、少なくとも７５％の２’－Ｏ－メチル修飾を含む；
（７）前記センス鎖の前記３’末端から７位、１０位、及び１１位の前記ヌクレオチドが、２’－メトキシ－リボヌクレオチドではない；
（８）前記センス鎖の前記５’末端から１～２位の前記ヌクレオチドが、ホスホロチオエートヌクレオチド間連結を介して互いに結合している、項９０に記載の分岐ＲＮＡ化合物。
［項１４１］機能部分が、前記アンチセンス鎖の前記５’末端及び／または３’末端に連結されている、項９３～１４０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１４２］機能部分が、前記センス鎖の前記５’末端及び／または３’末端に連結されている、項９３～１４０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１４３］機能部分が、前記センス鎖の前記３’末端に連結されている、項９３～１４０のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１４４］前記機能部分が、疎水性部分を含む、項１４１～１４３のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１４５］前記疎水性部分が、脂肪酸、ステロイド、セコステロイド、脂質、ガングリオシド、ヌクレオシド類似体、エンドカンナビノイド、ビタミン、及びそれらの混合物からなる群から選択される、項１４４に記載の分岐ＲＮＡ化合物。
［項１４６］前記ステロイドが、コレステロール及びリトコール酸（ＬＣＡ）からなる群から選択される、項１４５に記載の分岐ＲＮＡ化合物。
［項１４７］前記脂肪酸が、エイコサペンタエン酸（ＥＰＡ）、ドコサヘキサエン酸（ＤＨＡ）、及びドコサン酸（ＤＣＡ）からなる群から選択される、項１４５に記載の分岐ＲＮＡ化合物。
［項１４８］前記ビタミンが、コリン、ビタミンＡ、ビタミンＥ、それらの誘導体、及びそれらの代謝物からなる群から選択される、項１４５に記載の分岐ＲＮＡ化合物。
［項１４９］前記ビタミンが、レチノイン酸及びコハク酸アルファ－トコフェロールからなる群から選択される、項１４５に記載の分岐ＲＮＡ化合物。
［項１５０］前記機能部分が、リンカーにより前記アンチセンス鎖及び／またはセンス鎖に連結されている、項１４１～１４９のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１５１］前記リンカーが、二価または三価のリンカーを含む、項１５０に記載の分岐ＲＮＡ化合物。
［項１５２］前記二価または三価のリンカーが、

（式中、ｎは、１、２、３、４、または５である）からなる群から選択される、項１５１に記載の分岐ＲＮＡ化合物。
［項１５３］前記リンカーが、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスホジエステル、ホスホロチオエート、ホスホルアミデート、アミド、カルバメート、またはそれらの組み合わせを含む、項１５０または１５２に記載の分岐ＲＮＡ化合物。
［項１５４］前記リンカーが、三価リンカーである場合、前記リンカーは、ホスホジエステルまたはホスホジエステル誘導体をさらに連結する、項１５１に記載の分岐ＲＮＡ化合物。
［項１５５］前記ホスホジエステルまたはホスホジエステル誘導体が、以下からなる群から選択される、項１５１に記載の分岐ＲＮＡ化合物：

（式中、Ｘは、Ｏ、ＳまたはＢＨ _３である）。
［項１５６］センス鎖の前記３’末端から１位及び２位の前記ヌクレオチド、及びアンチセンス鎖の前記５’末端から１位及び２位の前記ヌクレオチドが、ホスホロチオエート結合を介して隣接するリボヌクレオチドに結合される、項９３～１５５のいずれか一項に記載の分岐ＲＮＡ化合物。
［項１５７］式（Ｉ）の化合物：

（式中：
Ｌは、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスフェート、ホスホネート、ホスホルアミデート、エステル、アミド、トリアゾール、またはそれらの組み合わせを含み；並びに式（Ｉ）は任意選択で、１つまたは複数の分岐点Ｂ、及び１つまたは複数のスペーサーＳを含み、
Ｂは出現ごとに独立して、多価有機種またはその誘導体であり、
Ｓは、各出現ごとに独立して、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスフェート、ホスホネート、ホスホルアミデート、エステル、アミド、トリアゾール、またはそれらの組み合わせを含み、
Ｎは、センス鎖及びアンチセンス鎖を含む長さ１５～３５塩基を含む二本鎖核酸であり；ここで
前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的な配列を含み；
前記センス鎖及びアンチセンス鎖は、それぞれ独立して、１つ以上の化学修飾を含み；
ｎは、２、３、４、５、６、７、または８である）。
［項１５８］式（Ｉ－１）～（Ｉ－９）から選択される構造を有する、項１５７に記載の化合物：

［項１５９］前記アンチセンス鎖が、以下からなる群から選択される５’末端基Ｒを含む、項１５７記載の化合物：

［項１６０］式（ＩＩ）の構造を有する、項１５７に記載の化合物：

（式中、
Ｘは、出現ごとに独立して、アデノシン、グアノシン、ウリジン、シチジン、及びそれらの化学修飾誘導体から選択され、
Ｙは、出現ごとに独立して、アデノシン、グアノシン、ウリジン、シチジン、及びそれらの化学修飾誘導体から選択され、
－は、ホスホジエステルヌクレオシド間連結を表し；
＝は、ホスホロチオエートヌクレオシド間連結を表し；
－－－は、出現ごとに独立して、塩基対相互作用またはミスマッチを表す）。
［項１６１］式（ＩＶ）の構造を有する、項１５７に記載の化合物：

（式中、
Ｘは、出現ごとに独立して、アデノシン、グアノシン、ウリジン、シチジン、及びそれらの化学修飾誘導体から選択され、
Ｙは、出現ごとに独立して、アデノシン、グアノシン、ウリジン、シチジン、及びそれらの化学修飾誘導体から選択され、
－は、ホスホジエステルヌクレオシド間連結を表し；
＝は、ホスホロチオエートヌクレオシド間連結を表し；
－－－は、出現ごとに独立して、塩基対相互作用またはミスマッチを表す）。
［項１６２］Ｌが構造Ｌ１である、項１５７～１６１のいずれか一項に記載の化合物：

［項１６３］ＲがＲ ^３であり、ｎが２である、項１６２に記載の化合物。
［項１６４］Ｌが構造Ｌ２である、項１５７～１６１のいずれか一項に記載の化合物：

［項１６５］ＲがＲ ^３であり、ｎが２である、項１６４に記載の化合物。
［項１６６］式（ＶＩ）の構造を有する治療用核酸のための送達系：

（式中、
Ｌは、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスフェート、ホスホネート、ホスホルアミデート、エステル、アミド、トリアゾール、またはそれらの組み合わせを含み、式（ＶＩ）は、１つ以上の分岐点Ｂ、及び１つ以上のスペーサーＳをさらに含み、式中、
Ｂは、出現ごとに独立して、多価有機種またはその誘導体を含み；
Ｓは、出現ごとに独立して、エチレングリコール鎖、アルキル鎖、ペプチド、ＲＮＡ、ＤＮＡ、ホスフェート、ホスホネート、ホスホルアミデート、エステル、アミド、トリアゾール、またはそれらの組み合わせを含み；
各ｃＮＡは、独立して、１つ以上の化学修飾を含むキャリア核酸であり、
各ｃＮＡは、独立して、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列の少なくとも１５の連続ヌクレオチドを含み；
ｎは、２、３、４、５、６、７、または８である）。
［項１６７］式（ＶＩ－１）～（ＶＩ－９）から選択される構造を有する、項１６６に記載の送達系：

［項１６８］各ｃＮＡが、独立して、化学修飾ヌクレオチドを含む、項１６６に記載の送達系。
［項１６９］ｎ個の治療用核酸（ＮＡ）をさらに含み、各ＮＡは、少なくとも１つのｃＮＡにハイブリダイズする、項１６６に記載の送達系。
［項１７０］各ＮＡが独立して、少なくとも１６の連続ヌクレオチドを含む、項１６９に記載の送達系。
［項１７１］各ＮＡが、独立して、少なくとも１６～２０の連続ヌクレオチドを含む、項１７０に記載の送達系。
［項１７２］各ＮＡが、少なくとも２ヌクレオチドの不対オーバーハングを含む、項１６９に記載の送達系。
［項１７３］前記オーバーハングの前記ヌクレオチドが、ホスホロチオエート連結を介して結合されている、項１７２に記載の送達系。
［項１７４］各ＮＡが、独立して、ＤＮＡ、ｓｉＲＮＡ、ａｎｔａｇｏｍｉＲ、ｍｉＲＮＡ、ギャップマー、ミックスマー、及びガイドＲＮＡからなる群から選択される、項１６９に記載の送達系。
［項１７５］各ＮＡが、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列に実質的に相補的である、項１６９に記載の送達系。
［項１７６］項８５～１６５のいずれか一項に記載の化合物または項１６６～１７５のいずれかに記載の系、及び薬学的に許容される担体を含む、生物におけるＭＳＨ３遺伝子の発現を阻害するための医薬組成物。
［項１７７］前記化合物または前記系が、前記ＭＳＨ３遺伝子の前記発現を少なくとも５０％阻害する、項１７６に記載の医薬組成物。
［項１７８］前記化合物または前記系が、前記ＭＳＨ３遺伝子の前記発現を少なくとも８０％阻害する、項１７６に記載の医薬組成物。
［項１７９］細胞におけるＭＳＨ３遺伝子の発現を阻害するための方法であって、
（ａ）項８５～１６５のいずれか一項に記載の化合物または項１６６～１７５のいずれか一項に記載の系を前記細胞に導入するステップと；
（ｂ）ステップ（ａ）で産生された前記細胞を、前記ＭＳＨ３遺伝子の前記ｍＲＮＡ転写物の分解を得るのに十分な時間維持し、それによって前記細胞中の前記ＭＳＨ３遺伝子の発現を阻害することと、を含む、前記方法。
［項１８０］神経変性疾患を治療または管理する方法であって、こうした治療または管理を必要とする患者に、治療有効量の項８５～１６５のいずれか一項に記載の化合物または項１６６～１７５のいずれか一項に記載の系を投与することを含む、前記方法。
［項１８１］前記ｄｓＲＮＡが、前記患者の脳に投与される、項１８０に記載の方法。
［項１８２］前記ｄｓＲＮＡが、脳・脳室内（ＩＣＶ）注射、線条体内（ＩＳ）注射、静脈内（ＩＶ）注射、皮下（ＳＱ）注射、またはそれらの組み合わせによって投与される、項１８０に記載の方法。
［項１８３］前記ｄｓＲＮＡを投与することは、海馬、線条体、皮質、小脳、視床、視床下部、及び脊髄のうちの１つ以上において、前記ＭＳＨ３遺伝子ｍＲＮＡの減少を引き起こす、項１８０に記載の方法。
［項１８４］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも５０％阻害する、項１７９～１８３のいずれか一項に記載の方法。
［項１８５］前記ｄｓＲＮＡが、前記ＭＳＨ３遺伝子の前記発現を少なくとも８０％阻害する、項１７９～１８３のいずれか一項に記載の方法。
［項１８６］細胞におけるＨＴＴｍＲＮＡを低減するための方法であって、
（ａ）ＭＳＨ３核酸配列と実質的に相補的な配列を含むオリゴヌクレオチドを前記細胞に導入することと、
（ｂ）前記ＨＴＴｍＲＮＡの分解を得るのに十分な時間、ステップ（ａ）で産生された前記細胞を維持し、それによって前記細胞中のＨＴＴｍＲＮＡを低減することと、
を含む、前記方法。
［項１８７］前記オリゴヌクレオチドが、センス鎖及びアンチセンス鎖を含む二本鎖ＲＮＡ（ｄｓＲＮＡ）分子を含み、
前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列と実質的に相補的な配列を含む、項１８６に記載の方法。
［項１８８］前記アンチセンス鎖が、配列番号１３～１８及び３１～４２のいずれか１つのＭＳＨ３核酸配列と実質的に相補的な配列を含む、項１８７に記載の方法。
［項１８９］細胞におけるＨＴＴｍＲＮＡを低減するための方法であって、
（ａ）項１～６７のいずれか一項に記載のｄｓＲＮＡ、項７８～８２のいずれか一項に記載のベクター、項８５～１６５のいずれか一項に記載の化合物、または項１６６～１７５のいずれか一項に記載のシステムを前記細胞に導入することと、
（ｂ）前記ＨＴＴｍＲＮＡの分解を得るのに十分な時間、ステップ（ａ）で産生された前記細胞を維持し、それによって前記細胞中のＨＴＴｍＲＮＡを低減することと、
を含む、前記方法。
［項１９０］前記ＨＴＴｍＲＮＡが、ＨＴＴ１ａｍＲＮＡを含む、項１８６～１８９のいずれか一項に記載の方法。
［項１９１］前記ＨＴＴ１ａｍＲＮＡが、配列番号４３に記載の核酸配列を含む、項１９０に記載の方法。
［項１９２］ハンチントン病（ＨＤ）を治療または管理する方法であって、ＭＳＨ３核酸配列と実質的に相補的な配列を含む治療有効量のオリゴヌクレオチドを、そのような治療または管理を必要とする患者に投与することを含む、前記方法。
［項１９３］トリヌクレオチドリピート疾患または障害を治療または管理する方法であって、ＭＳＨ３核酸配列と実質的に相補的な配列を含む治療有効量のオリゴヌクレオチドを、そのような治療または管理を必要とする患者に投与することを含む、前記方法。
［項１９４］前記オリゴヌクレオチドが、センス鎖及びアンチセンス鎖を含む二本鎖ＲＮＡ（ｄｓＲＮＡ）分子を含み、
前記アンチセンス鎖が、配列番号１～６及び１９～３０のいずれか１つのＭＳＨ３核酸配列と実質的に相補的な配列を含む、
項１９２または１９３に記載の方法。
［項１９５］前記アンチセンス鎖が、配列番号１３～１８及び３１～４２のいずれか１つのＭＳＨ３核酸配列と実質的に相補的な配列を含む、
項１９４に記載の方法。
［項１９６］ハンチントン病（ＨＤ）を治療または管理する方法であって、
項１～６７のいずれか一項に記載のｄｓＲＮＡ、項７８～８２のいずれか一項に記載のベクター、項８５～１６５のいずれか一項に記載の化合物、または項１６６～１７５のいずれか一項に記載のシステムの治療有効量をそのような治療または管理を必要とする患者に投与することを含む、前記方法。
［項１９７］トリヌクレオチドリピート疾患または障害を治療または管理する方法であって、
項１～６７のいずれか一項に記載のｄｓＲＮＡ、項７８～８２のいずれか一項に記載のベクター、項８５～１６５のいずれか一項に記載の化合物、または項１６６～１７５のいずれか一項に記載のシステムの治療有効量をそのような治療または管理を必要とする患者に投与することを含む、前記方法。 Equivalents The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative and not limiting of the present disclosure. The scope of the present disclosure is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Aspects of the invention include the following.
[Item 1] A double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand,
The molecule, wherein the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 2] The dsRNA according to item 1, wherein the antisense strand comprises a sequence substantially complementary to the MSH3 nucleic acid sequence set forth in any one of SEQ ID NOs: 13 to 18 and 31 to 42.
[Item 3] The dsRNA of item 1, comprising complementarity to at least 10, 11, 12, or 13 consecutive nucleotides of the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 4] The dsRNA of item 1 or 3, which contains three or fewer mismatches with the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 5] The dsRNA of item 1, comprising perfect complementarity to the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 6] The dsRNA of any one of items 1 to 5, wherein the antisense strand comprises about 15 to 25 nucleotides in length.
[Item 7] The dsRNA of any one of items 1 to 6, wherein the sense strand comprises about 15 to 25 nucleotides in length.
[Item 8] The dsRNA of any one of items 1 to 7, wherein the antisense strand is 20 nucleotides in length.
[Item 9] The dsRNA of any one of items 1 to 7, wherein the antisense strand is 21 nucleotides in length.
[Item 10] The dsRNA of any one of items 1 to 7, wherein the antisense strand is 22 nucleotides in length.
[Item 11] The dsRNA of any one of items 1 to 10, wherein the sense strand is 15 nucleotides in length.
[Item 12] The dsRNA of any one of items 1 to 10, wherein the sense strand is 16 nucleotides in length.
[Item 13] The dsRNA of any one of items 1 to 10, wherein the sense strand is 18 nucleotides in length.
[Item 14] The dsRNA of any one of items 1 to 10, wherein the sense strand is 20 nucleotides in length.
[Item 15] The dsRNA according to any one of items 1 to 14, comprising a double-stranded region of 15 to 20 base pairs.
[Item 16] The dsRNA of any one of items 1 to 15, comprising a double-stranded region of 15 base pairs.
[Item 17] The dsRNA of any one of items 1 to 15, comprising a double-stranded region of 16 base pairs.
[Item 18] The dsRNA of any one of items 1 to 15, comprising an 18-base pair double-stranded region.
[Item 19] The dsRNA of any one of items 1 to 15, comprising a 20 base pair double-stranded region.
[Item 20] The dsRNA of any one of items 1 to 19, wherein the dsRNA comprises a blunt end.
[Item 21] The dsRNA of any one of items 1 to 20, wherein the dsRNA comprises at least one single-stranded nucleotide overhang.
[Item 22] The dsRNA of Item 21, wherein the dsRNA comprises a single-stranded nucleotide overhang of about 2 to 5 nucleotides.
[Item 23] The dsRNA of Item 21, wherein the dsRNA comprises a single-stranded nucleotide overhang of 2 nucleotides.
[Item 24] The dsRNA of Item 21, wherein the dsRNA comprises a single-stranded nucleotide overhang of 5 nucleotides.
[Item 25] The dsRNA of any one of items 1 to 24, wherein the dsRNA comprises naturally occurring nucleotides.
[Item 26] The dsRNA of any one of items 1 to 24, wherein the dsRNA comprises at least one modified nucleotide.
[Item 27] The dsRNA according to Item 26, wherein the modified nucleotide comprises a 2'-O-methyl modified nucleotide, a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base containing nucleotide, or a mixture thereof.
[Item 28] The dsRNA of any one of items 1 to 27, wherein the dsRNA comprises at least one modified internucleotide linkage.
[Item 29] The dsRNA of item 28, wherein the modified internucleotide linkage comprises a phosphorothioate internucleotide linkage.
[Item 30] The dsRNA of any one of items 1 to 29, comprising from 4 to 16 phosphorothioate internucleotide linkages.
[Item 31] The dsRNA of any one of items 1 to 29, comprising from 8 to 13 phosphorothioate internucleotide linkages.
[Item 32] The dsRNA of any one of items 1 to 28, wherein the dsRNA comprises at least one modified internucleotide linkage of Formula I:

(Wherein,
B is a base pair moiety;
W is selected from the group consisting of O, OCH2, OCH, CH2, _and CH _;
X is selected from the group consisting of halo, hydroxy, and C _1-6 alkoxy;
Y is selected from the group consisting of O ⁻ , OH, OR, NH ⁻ , NH ₂ , S ⁻ , and SH;
Z is selected from the group consisting of O and _CH2 ;
R is a protecting group;

is an optional double bond).
[Item 33] The dsRNA of any one of Items 1 to 32, wherein the dsRNA comprises at least 80% chemically modified nucleotides.
[Item 34] The dsRNA of any one of items 1 to 33, wherein the dsRNA is fully chemically modified.
[Item 35] The dsRNA of any one of items 1 to 33, wherein the dsRNA contains at least 70% 2'-O-methyl nucleotide modifications.
[Item 36] The dsRNA of any one of items 1 to 33, wherein the antisense strand comprises at least 70% 2'-O-methyl nucleotide modifications.
[Item 37] The dsRNA of Item 36, wherein the antisense strand comprises 70% to 90% 2'-O-methyl nucleotide modifications.
[Item 38] The dsRNA of any one of items 1 to 33, wherein the sense strand comprises at least 65% 2'-O-methyl nucleotide modifications.
[Item 39] The dsRNA of Item 38, wherein the sense strand comprises 100% 2'-O-methyl nucleotide modifications.
[Item 40] The dsRNA of any one of items 1 to 39, wherein the sense strand comprises one or more nucleotide mismatches between the antisense strand and the sense strand.
[Item 41] The dsRNA of Item 40, wherein the one or more nucleotide mismatches are present at positions 2, 6, and 12 from the 5' end of the sense strand.
[Item 42] The dsRNA of Item 40, wherein the nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand.
[Item 43] The dsRNA of any one of items 1 to 42, wherein the antisense strand comprises a 5' phosphate, a 5'-alkyl phosphonate, a 5' alkylene phosphonate, or a 5' alkenyl phosphonate.
[Item 44] The dsRNA of Item 43, wherein the antisense strand comprises a 5' vinyl phosphonate.
[Item 45] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(7) The dsRNA, wherein the nucleotides at positions 1 and 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 46] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 70% 2'-O-methyl modifications;
(3) the nucleotide at position 14 from the 5' end of the antisense strand is not a 2'-methoxy-ribonucleotide;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 70% 2'-O-methyl modifications;
(7) The dsRNA, wherein the nucleotides at positions 1 and 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 47] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 85% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The dsRNA, wherein the nucleotides at positions 1 and 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 48] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The dsRNA, wherein the nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 49] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The dsRNA, wherein the nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 50] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 65% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 9, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) The dsRNA, wherein the nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 51] The dsRNA of item 1, comprising an antisense strand and a sense strand, each strand having a 5' end and a 3' end,
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 75% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) The dsRNA, wherein the nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 52] The dsRNA of any one of items 1 to 51, wherein a functional moiety is linked to the 5' end and/or the 3' end of the antisense strand.
[Item 53] The dsRNA of any one of items 1 to 51, wherein a functional moiety is linked to the 5' end and/or the 3' end of the sense strand.
[Item 54] The dsRNA of any one of items 1 to 51, wherein a functional moiety is linked to the 3' end of the sense strand.
[Item 55] The dsRNA of any one of Items 52 to 54, wherein the functional portion comprises a hydrophobic portion.
56. The dsRNA of claim 55, wherein the hydrophobic moiety is selected from the group consisting of fatty acids, steroids, secosteroids, lipids, gangliosides, nucleoside analogs, endocannabinoids, vitamins, and mixtures thereof.
[Item 57] The dsRNA of item 56, wherein the steroid is selected from the group consisting of cholesterol and lithocholic acid (LCA).
[Item 58] The dsRNA of Item 56, wherein the fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosanoic acid (DCA).
[Item 59] The dsRNA of Item 56, wherein the vitamin is selected from the group consisting of choline, vitamin A, vitamin E, and derivatives or metabolites thereof.
[Item 60] The dsRNA of Item 59, wherein the vitamin is selected from the group consisting of retinoic acid and alpha-tocopherol succinate.
[Item 61] The dsRNA of any one of Items 54 to 60, wherein the functional moiety is linked to the antisense strand and/or the sense strand by a linker.
[Item 62] The dsRNA of item 61, wherein the linker comprises a bivalent or trivalent linker.
[Item 63] The bivalent or trivalent linker is

(wherein n is 1, 2, 3, 4, or 5).
[Item 64] The dsRNA of Items 61 or 62, wherein the linker comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, or a combination thereof.
[Item 65] The dsRNA of Items 62 or 63, wherein when the linker is a trivalent linker, the linker further links a phosphodiester or phosphodiester derivative.
[Item 66] The dsRNA of item 65, wherein the phosphodiester or phosphodiester derivative is selected from the group consisting of:

(wherein X is O, S or BH3 ₎ .
[Item 67] The dsRNA of any one of items 1 to 66, wherein the nucleotides 1 and 2 from the 3' end of the sense strand and the nucleotides 1 and 2 from the 5' end of the antisense strand are linked to adjacent ribonucleotides via phosphorothioate bonds.
[Item 68] A pharmaceutical composition for inhibiting expression of the MSH3 gene in an organism, comprising the dsRNA of any one of items 1 to 67 and a pharma- ceutically acceptable carrier.
[Item 69] The pharmaceutical composition of item 68, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 50%.
[Item 70] The pharmaceutical composition of item 68, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 80%.
[Item 71] A method for regulating expression of the MSH3 gene in a cell, comprising:
(a) introducing into the cell the double-stranded ribonucleic acid (dsRNA) according to any one of paragraphs 1 to 67;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene, thereby inhibiting expression of the MSH3 gene in the cells.
[Item 72] A method for treating or managing a neurodegenerative disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of the dsRNA of any one of items 1 to 67.
73. The method of claim 72, wherein the dsRNA is administered to the brain of the patient.
[Item 74] The method of item 72, wherein the dsRNA is administered by intracerebroventricular (ICV) injection, intrastriatal (IS) injection, intravenous (IV) injection, subcutaneous (SQ) injection, or a combination thereof.
[Item 75] The method of item 72, wherein administering the dsRNA causes a decrease in MSH3 gene mRNA in one or more of the hippocampus, striatum, cortex, cerebellum, thalamus, hypothalamus, and spinal cord.
76. The method of any one of claims 71 to 75, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 50%.
77. The method of any one of claims 71 to 75, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 80%.
78. A vector comprising a regulatory sequence operably linked to a nucleotide sequence encoding a dsRNA molecule substantially complementary to an MSH3 nucleic acid sequence of SEQ ID NO: 1-6 and 19-30.
79. The vector of claim 78, wherein the RNA molecule inhibits the expression of the MSH3 gene by at least 30%.
80. The vector of claim 78, wherein the RNA molecule inhibits the expression of the MSH3 gene by at least 50%.
81. The vector of claim 78, wherein the RNA molecule inhibits the expression of the MSH3 gene by at least 80%.
[Item 82] The vector of item 78, wherein the dsRNA comprises a sense strand and an antisense strand, and the antisense strand comprises a sequence substantially complementary to the MSH3 nucleic acid sequence of SEQ ID NOs: 1-6 and 19-30.
[Item 83] A cell comprising the vector according to any one of Items 78 to 82.
[Item 84] A recombinant adeno-associated virus (rAAV), comprising the vector according to any one of Items 78 to 82 and an AAV capsid.
[Item 85] A branched RNA compound comprising two or more of the dsRNA molecules of any one of items 1 to 67, which are covalently linked to each other.
86. The branched RNA compound of claim 85, wherein the dsRNA molecules are covalently linked to each other by a linker, spacer, or branch point.
[Item 87] Two or more RNA molecules comprising 15 to 35 nucleotides in length, and
comprising a sequence substantially complementary to MSH3 mRNA;
A branched RNA compound, wherein the two RNA molecules are linked to each other by one or more moieties independently selected from a linker, a spacer, and a branch point.
[Item 88] The branched RNA compound of item 87, comprising a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30.
[Item 89] The branched RNA compound of item 87, comprising a nucleic acid sequence substantially complementary to one or more of the MSH3 nucleic acid sequences of any one of SEQ ID NOs: 13-18 and 31-42.
[Item 90] The branched RNA compound of any one of Items 87 to 89, wherein the RNA molecule comprises one or both of ssRNA and dsRNA.
[Item 91] The branched RNA compound of any one of Items 87 to 90, wherein the RNA molecule comprises an antisense oligonucleotide.
[Item 92] The branched RNA compound of any one of Items 87 to 91, wherein each RNA molecule comprises 15 to 25 nucleotides in length.
[Item 93] The branched RNA compound of any one of Items 87 to 90, wherein each RNA molecule comprises a dsRNA comprising a sense strand and an antisense strand, and each antisense strand independently comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30.
[Item 94] The branched RNA compound of item 93, comprising complementarity to at least 10, 11, 12, or 13 consecutive nucleotides of the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 95] The branched RNA compound of item 93, wherein each RNA molecule contains no more than three mismatches with the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 96] The branched RNA compound of item 93, comprising substantially perfect complementarity to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30.
[Item 97] The branched RNA compound of any one of Items 93 to 96, wherein the antisense strand comprises a portion having the nucleic acid sequence of any one of SEQ ID NOs: 7 to 12.
[Item 98] The branched RNA compound of any one of Items 93 to 97, wherein the antisense strand and/or the sense strand comprises about 15 nucleotides to 25 nucleotides in length.
[Item 99] The branched RNA compound of any one of Items 93 to 98, wherein the antisense strand is 20 nucleotides in length.
[Item 100] The branched RNA compound of any one of Items 93 to 98, wherein the antisense strand is 21 nucleotides in length.
[Item 101] The branched RNA compound of any one of Items 93 to 98, wherein the antisense strand is 22 nucleotides in length.
[Item 102] The branched RNA compound of any one of Items 93 to 101, wherein the sense strand is 15 nucleotides in length.
[Item 103] The branched RNA compound of any one of Items 93 to 101, wherein the sense strand is 16 nucleotides in length.
[Item 104] The branched RNA compound of any one of Items 93 to 101, wherein the sense strand is 18 nucleotides in length.
[Item 105] The branched RNA compound of any one of Items 93 to 101, wherein the sense strand is 20 nucleotides in length.
[Item 106] The branched RNA compound of any one of Items 90 to 105, wherein the dsRNA comprises a double-stranded region of 15 to 20 base pairs.
[Item 107] The branched RNA compound of any one of Items 90 to 106, wherein the dsRNA comprises a double-stranded region of 15 base pairs.
[Item 108] The branched RNA compound of any one of Items 90 to 106, wherein the dsRNA comprises a double-stranded region of 16 base pairs.
[Item 109] The branched RNA compound of any one of Items 90 to 106, wherein the dsRNA comprises an 18 base pair double-stranded region.
[Item 110] The branched RNA compound of any one of Items 90 to 106, wherein the dsRNA comprises a 20 base pair double-stranded region.
[Item 111] The branched RNA compound of any one of items 90 to 110, wherein the dsRNA comprises blunt ends.
[Item 112] The branched RNA compound of any one of Items 90 to 110, wherein the dsRNA comprises at least one single-stranded nucleotide overhang.
[Item 113] The branched RNA compound of any one of Items 90 to 112, wherein the dsRNA comprises a single-stranded nucleotide overhang of 2 to 5 nucleotides.
[Item 114] The branched RNA compound of any one of Items 90 to 113, wherein the dsRNA comprises naturally occurring nucleotides.
[Item 115] The branched RNA compound of any one of Items 90 to 114, wherein the dsRNA comprises at least one modified nucleotide.
[Item 116] The branched RNA compound of Item 115, wherein the modified nucleotide comprises a 2'-O-methyl modified nucleotide, a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base containing nucleotide.
[Item 117] The branched RNA compound of any one of Items 90 to 116, wherein the dsRNA comprises at least one modified internucleotide linkage.
[Item 118] The branched RNA compound of item 117, wherein the modified internucleotide linkage comprises a phosphorothioate internucleotide linkage.
[Item 119] The branched RNA compound of any one of Items 90 to 118, comprising 4 to 16 phosphorothioate internucleotide linkages.
[Item 120] The branched RNA compound of any one of Items 90 to 118, comprising from 8 to 13 phosphorothioate internucleotide linkages.
[Item 121] The branched RNA compound of any one of items 90 to 117, wherein the dsRNA comprises at least one modified internucleotide linkage of formula (I):

is an optional double bond).
[Item 122] The branched RNA compound of any one of Items 90 to 121, wherein the dsRNA comprises at least 80% chemically modified nucleotides.
[Item 123] The branched RNA compound of any one of Items 90 to 121, wherein the dsRNA is fully chemically modified.
124. The branched RNA compound of any one of claims 90 to 121, wherein the dsRNA contains at least 70% 2'-O-methyl nucleotide modifications.
[Item 125] The branched RNA compound of any one of Items 90 to 124, wherein the antisense strand contains at least 70% 2'-O-methyl nucleotide modifications.
126. The branched RNA compound of claim 125, wherein the antisense strand comprises 70% to 90% 2'-O-methyl nucleotide modifications.
[Item 127] The branched RNA compound of any one of Items 90 to 124, wherein the sense strand contains at least 65% 2'-O-methyl nucleotide modifications.
128. The branched RNA compound of claim 127, wherein the sense strand contains 100% 2'-O-methyl nucleotide modifications.
[Item 129] The branched RNA compound of any one of Items 93 to 128, wherein the sense strand contains one or more nucleotide mismatches between the antisense strand and the sense strand.
[Item 130] The branched RNA compound of Item 129, wherein the one or more nucleotide mismatches are present at positions 2, 6, and 12 from the 5' end of the sense strand.
[Item 131] The branched RNA compound of Item 129, wherein the nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand.
[Item 132] The branched RNA compound of any one of Items 93 to 131, wherein the antisense strand comprises a 5' phosphate, a 5'-alkyl phosphonate, a 5' alkylene phosphonate, a 5' alkenyl phosphonate, or a mixture thereof.
[Item 133] The branched RNA compound of Item 132, wherein the antisense strand comprises a 5' vinyl phosphonate.
[Item 134] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(7) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 135] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 70% 2'-O-methyl modifications;
(3) the nucleotide at position 14 from the 5' end of the antisense strand is not a 2'-methoxy-ribonucleotide;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 70% 2'-O-methyl modifications;
(7) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 136] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 85% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 137] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 138] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 139] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 65% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 9, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
[Item 140] The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 75% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) The branched RNA compound according to item 90, wherein the nucleotides at positions 1-2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
141. The branched RNA compound of any one of claims 93 to 140, wherein a functional moiety is linked to the 5' end and/or the 3' end of the antisense strand.
[Item 142] The branched RNA compound of any one of Items 93 to 140, wherein a functional moiety is linked to the 5' end and/or the 3' end of the sense strand.
[Item 143] The branched RNA compound of any one of Items 93 to 140, wherein a functional moiety is linked to the 3' end of the sense strand.
[Item 144] The branched RNA compound of any one of items 141 to 143, wherein the functional moiety comprises a hydrophobic moiety.
145. The branched RNA compound of claim 144, wherein the hydrophobic moiety is selected from the group consisting of fatty acids, steroids, secosteroids, lipids, gangliosides, nucleoside analogs, endocannabinoids, vitamins, and mixtures thereof.
146. The branched RNA compound of claim 145, wherein the steroid is selected from the group consisting of cholesterol and lithocholic acid (LCA).
147. The branched RNA compound of claim 145, wherein the fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosanoic acid (DCA).
[Item 148] The branched RNA compound of Item 145, wherein the vitamin is selected from the group consisting of choline, vitamin A, vitamin E, derivatives thereof, and metabolites thereof.
149. The branched RNA compound of claim 145, wherein the vitamin is selected from the group consisting of retinoic acid and alpha-tocopherol succinate.
[Item 150] The branched RNA compound of any one of Items 141 to 149, wherein the functional moiety is linked to the antisense strand and/or the sense strand by a linker.
[Item 151] The branched RNA compound of item 150, wherein the linker comprises a bivalent or trivalent linker.
[Item 152] The bivalent or trivalent linker,

152. The branched RNA compound of claim 151, selected from the group consisting of:
153. The branched RNA compound of claim 150 or 152, wherein the linker comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, or a combination thereof.
[Item 154] The branched RNA compound of item 151, wherein when the linker is a trivalent linker, the linker further links a phosphodiester or phosphodiester derivative.
[Item 155] The branched RNA compound of item 151, wherein the phosphodiester or phosphodiester derivative is selected from the group consisting of:

(wherein X is O, S or BH3 ₎ .
[Item 156] The branched RNA compound of any one of Items 93 to 155, wherein the nucleotides 1 and 2 from the 3' end of the sense strand and the nucleotides 1 and 2 from the 5' end of the antisense strand are linked to adjacent ribonucleotides via phosphorothioate linkages.
[Item 157] Compound of formula (I):

(Wherein:
L comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof; and formula (I) optionally comprises one or more branch points B, and one or more spacers S,
B is, independently at each occurrence, a polyvalent organic species or derivative thereof;
S, independently for each occurrence, comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof;
N is a double-stranded nucleic acid comprising a length of 15 to 35 bases, including a sense strand and an antisense strand;
the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
the sense strand and the antisense strand each independently comprise one or more chemical modifications;
n is 2, 3, 4, 5, 6, 7, or 8).
[Item 158] The compound according to item 157, having a structure selected from formulas (I-1) to (I-9):

[Item 159] The compound of item 157, wherein the antisense strand comprises a 5'-terminal group R selected from the group consisting of:

[Item 160] The compound according to item 157, having the structure of formula (II):

(Wherein,
X is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
Y is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
- represents a phosphodiester internucleoside linkage;
= represents a phosphorothioate internucleoside linkage;
--- represents, independently at each occurrence, a base pair interaction or a mismatch).
[Item 161] The compound according to item 157, having the structure of formula (IV):

(Wherein,
X is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
Y is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
- represents a phosphodiester internucleoside linkage;
= represents a phosphorothioate internucleoside linkage;
--- represents, independently at each occurrence, a base pair interaction or a mismatch).
[Item 162] The compound according to any one of items 157 to 161, wherein L is structure L1:

[Item 163] The compound according to item 162, wherein R is R3 ^and n is 2.
[Item 164] The compound according to any one of items 157 to 161, wherein L is structure L2:

[Item 165] The compound according to item 164, wherein R is R3 ^and n is 2.
[Item 166] A delivery system for a therapeutic nucleic acid having the structure of formula (VI):

(Wherein,
L comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof, and formula (VI) further comprises one or more branch points B, and one or more spacers S, wherein
B comprises, independently at each occurrence, a polyvalent organic species or derivative thereof;
S, independently at each occurrence, comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof;
each cNA is independently a carrier nucleic acid that contains one or more chemical modifications;
each cNA independently comprises at least 15 contiguous nucleotides of the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30;
n is 2, 3, 4, 5, 6, 7, or 8).
[Item 167] The delivery system according to Item 166, having a structure selected from formulas (VI-1) to (VI-9):

[Item 168] The delivery system of Item 166, wherein each cNA independently comprises a chemically modified nucleotide.
[Item 169] The delivery system of Item 166, further comprising n therapeutic nucleic acids (NAs), each NA hybridizing to at least one cNA.
[Item 170] The delivery system of Item 169, wherein each NA independently comprises at least 16 consecutive nucleotides.
[Item 171] The delivery system of Item 170, wherein each NA independently comprises at least 16-20 contiguous nucleotides.
[Item 172] The delivery system of item 169, wherein each NA comprises an unpaired overhang of at least 2 nucleotides.
173. The delivery system of claim 172, wherein the nucleotides of the overhang are linked via phosphorothioate linkages.
[Item 174] The delivery system of Item 169, wherein each NA is independently selected from the group consisting of DNA, siRNA, antagomiR, miRNA, gapmer, mixmer, and guide RNA.
[Item 175] The delivery system of Item 169, wherein each NA is substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 176] A pharmaceutical composition for inhibiting expression of the MSH3 gene in an organism, comprising a compound according to any one of items 85 to 165 or a system according to any one of items 166 to 175, and a pharma- ceutically acceptable carrier.
177. The pharmaceutical composition of claim 176, wherein the compound or system inhibits the expression of the MSH3 gene by at least 50%.
178. The pharmaceutical composition of claim 176, wherein the compound or system inhibits the expression of the MSH3 gene by at least 80%.
179. A method for inhibiting expression of the MSH3 gene in a cell, comprising:
(a) introducing into said cell a compound according to any one of paragraphs 85 to 165 or a system according to any one of paragraphs 166 to 175;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene, thereby inhibiting expression of the MSH3 gene in the cells.
[Item 180] A method for treating or managing a neurodegenerative disease, comprising administering to a patient in need of such treatment or management a therapeutically effective amount of a compound according to any one of items 85 to 165 or a system according to any one of items 166 to 175.
[Item 181] The method of item 180, wherein the dsRNA is administered to the brain of the patient.
[182] The method of paragraph 180, wherein the dsRNA is administered by intracerebroventricular (ICV) injection, intrastriatal (IS) injection, intravenous (IV) injection, subcutaneous (SQ) injection, or a combination thereof.
183. The method of claim 180, wherein administering the dsRNA causes a decrease in the MSH3 gene mRNA in one or more of the hippocampus, striatum, cortex, cerebellum, thalamus, hypothalamus, and spinal cord.
[Item 184] The method of any one of Items 179 to 183, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 50%.
[Item 185] The method of any one of Items 179-183, wherein the dsRNA inhibits the expression of the MSH3 gene by at least 80%.
186. A method for reducing HTT mRNA in a cell, comprising:
(a) introducing into said cell an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the HTT mRNA, thereby reducing HTT mRNA in the cells;
The method comprising:
[Item 187] The oligonucleotide comprises a double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand,
187. The method of Paragraph 186, wherein the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.
[Item 188] The method of Item 187, wherein the antisense strand comprises a sequence substantially complementary to the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 13-18 and 31-42.
189. A method for reducing HTT mRNA in a cell, comprising:
(a) introducing into the cell a dsRNA according to any one of paragraphs 1 to 67, a vector according to any one of paragraphs 78 to 82, a compound according to any one of paragraphs 85 to 165, or a system according to any one of paragraphs 166 to 175;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the HTT mRNA, thereby reducing HTT mRNA in the cells;
The method comprising:
[Item 190] The method of any one of Items 186 to 189, wherein the HTT mRNA comprises HTT1a mRNA.
[Item 191] The method of Item 190, wherein the HTT1a mRNA comprises the nucleic acid sequence set forth in SEQ ID NO:43.
[Item 192] A method for treating or managing Huntington's disease (HD), comprising administering to a patient in need of such treatment or management a therapeutically effective amount of an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence.
193. A method for treating or managing a trinucleotide repeat disease or disorder, comprising administering to a patient in need of such treatment or management a therapeutically effective amount of an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence.
[Item 194] The oligonucleotide comprises a double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand,
The antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1 to 6 and 19 to 30;
194. The method according to claim 192 or 193.
[Item 195] The antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 13-18 and 31-42.
195. The method according to claim 194.
[Item 196] A method for treating or managing Huntington's disease (HD), comprising:
The method comprises administering a therapeutically effective amount of the dsRNA according to any one of paragraphs 1 to 67, the vector according to any one of paragraphs 78 to 82, the compound according to any one of paragraphs 85 to 165, or the system according to any one of paragraphs 166 to 175 to a patient in need of such treatment or management.
197. A method for treating or managing a trinucleotide repeat disease or disorder, comprising:
The method comprises administering a therapeutically effective amount of the dsRNA according to any one of paragraphs 1 to 67, the vector according to any one of paragraphs 78 to 82, the compound according to any one of paragraphs 85 to 165, or the system according to any one of paragraphs 166 to 175 to a patient in need of such treatment or management.

Claims

A double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand,
The molecule, wherein the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.

the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence set forth in any one of SEQ ID NOs: 13-18 and 31-42 ;
comprises complementarity to at least 10, 11, 12, or 13 consecutive nucleotides of the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30 ;
contains no more than three mismatches with the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30; or
2. The dsRNA of claim 1, comprising perfect complementarity to the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30.

3. The dsRNA of claim 1 or 2, wherein the antisense strand comprises about 15 to 25 nucleotides in length ; alternatively, the antisense strand is 20 nucleotides in length; alternatively, the antisense strand is 21 nucleotides in length; or alternatively, the antisense strand is 22 nucleotides in length .

The dsRNA of any one of claims 1 to 6, wherein the sense strand comprises between 15 and 25 nucleotides in length ; or is 15, 16, 18 or 20 nucleotides in length .

The dsRNA of any one of claims 1 to 4 , comprising a double-stranded region of 15 to 20 base pairs ; or a double-stranded region of 15, 16, 18 or 20 base pairs .

the dsRNA is blunt ended ; and/or
The dsRNA comprises at least one single-stranded nucleotide overhang, optionally a single-stranded nucleotide overhang of 2 to 5 nucleotides, or a single-stranded nucleotide overhang of 2 nucleotides, or a single-stranded nucleotide overhang of 5 nucleotides.
The dsRNA according to any one of claims 1 to 5 , comprising:

the dsRNA comprises naturally occurring nucleotides ; and/or
comprises at least one modified nucleotide;
7. The dsRNA of claim 1, wherein the modified nucleotides are 2'-O-methyl modified nucleotides, 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, non-natural base containing nucleotides, or mixtures thereof, and wherein the dsRNA comprises at least 80% chemically modified nucleotides, the dsRNA is fully chemically modified, the dsRNA comprises at least 70% 2'-O-methyl nucleotide modifications, the antisense strand comprises at least 70% 2'-O-methyl nucleotide modifications, or the antisense strand comprises 70%-90% 2'-O-methyl nucleotide modifications, and/or the sense strand comprises at least 65% 2'-O-methyl nucleotide modifications, and wherein the sense strand comprises 100% 2'-O-methyl nucleotide modifications .

the dsRNA comprises at least one modified internucleotide linkage, optionally wherein the modified internucleotide linkage comprises a phosphorothioate internucleotide linkage, optionally comprising between 4 and 16 phosphorothioate internucleotide linkages, or between 8 and 13 phosphorothioate internucleotide linkages, or
The dsRNA has Formula I:

is an optional double bond).
The dsRNA of any one of claims 1 to 7 , comprising at least one modified internucleotide linkage of the formula :

the sense strand comprises one or more nucleotide mismatches between the antisense strand and the sense strand, and optionally
the one or more nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand;
the nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand ;
A dsRNA described in any one of claims 1 to 8 .

the antisense strand comprises a 5' phosphate, a 5'-alkyl phosphonate, a 5' alkylene phosphonate, or a 5' alkenyl phosphonate, and optionally the antisense strand comprises a 5' vinyl phosphonate ;
A dsRNA described in any one of claims 1 to 9 .

a functional moiety is linked to the 5'-end and/or 3'-end of the antisense strand, to the 5'-end and 3'-end of the sense strand, to the 3'-end of the sense strand, and, optionally
the functional moiety comprises a hydrophobic moiety, and optionally
The hydrophobic moiety is selected from the group consisting of fatty acids, steroids, secosteroids, lipids, gangliosides, nucleoside analogs, endocannabinoids, vitamins, and mixtures thereof, and optionally:
the steroid is selected from the group consisting of cholesterol and lithocholic acid (LCA);
the fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosanoic acid (DCA);
The vitamin is selected from the group consisting of choline, vitamin A, vitamin E, and derivatives or metabolites thereof;
the vitamin is selected from the group consisting of retinoic acid and alpha-tocopherol succinate;
A dsRNA according to any one of claims 1 to 10 .

the functional moiety is linked to the antisense strand and/or the sense strand by a linker, and optionally
The linker comprises a bivalent or trivalent linker, and optionally
The bivalent or trivalent linker is

wherein n is 1, 2, 3, 4, or 5; or
the linker comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, or a combination thereof; or
When the linker is a trivalent linker, the linker further links a phosphodiester or phosphodiester derivative, and optionally
The phosphodiester or phosphodiester derivative is selected from the group consisting of:

(wherein X is O, S or _BH3 ).

The dsRNA described in claim 11 .

The dsRNA of any one of claims 1 to 12, wherein the nucleotides 1 and 2 from the 3' end of the sense strand and the nucleotides 1 and 2 from the 5' end of the antisense strand are linked to adjacent ribonucleotides via phosphorothioate bonds.

A method for modulating expression of the MSH3 gene in a cell in vitro , comprising:
(a) introducing into said cell a double-stranded ribonucleic acid (dsRNA) according to any one of claims 1 to 67;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene, thereby inhibiting expression of the MSH3 gene in the cells.

A pharmaceutical composition for treating or managing a neurodegenerative disease, comprising a dsRNA according to any one of claims 1 to 12, and optionally
The dsRNA is formulated to be administered to the brain of a patient;
the dsRNA is formulated to be administered by intracerebroventricular (ICV) injection, intrastriatal (IS) injection, intravenous (IV) injection, subcutaneous (SQ) injection, or a combination thereof; or
the dsRNA causes a decrease in MSH3 gene mRNA in one or more of the hippocampus, striatum, cortex, cerebellum, thalamus, hypothalamus, and spinal cord; and/or
the dsRNA inhibits the expression of the MSH3 gene by at least 50%, or inhibits the expression of the MSH3 gene by at least 80%;
Pharmaceutical compositions .

A regulatory sequence operably linked to a nucleotide sequence encoding a dsRNA molecule substantially complementary to the MSH3 nucleic acid sequence of SEQ ID NOs: 1-6 and 19-30 , and optionally
the RNA molecule inhibits the expression of the MSH3 gene by at least 30%, by at least 50%, or by at least 80%.
vector.

17. The vector of claim 16 , wherein the dsRNA comprises a sense strand and an antisense strand, and the antisense strand comprises a sequence substantially complementary to the MSH3 nucleic acid sequence of SEQ ID NOs: 1-6 and 19-30.

18. An in vitro cell comprising the vector of claim 16 or 17 .

18. A recombinant adeno-associated virus (rAAV) comprising the vector of claim 16 or 17 and an AAV capsid.

13. A method for the preparation of a dsRNA molecule comprising the steps of:
the dsRNA molecules are covalently linked to each other by a linker, spacer, or branch point;
Branched RNA compounds.

two or more RNA molecules comprising 15-35 nucleotides in length and a sequence substantially complementary to MSH3 mRNA;
A branched RNA compound, wherein the two RNA molecules are linked to each other by one or more moieties independently selected from a linker, a spacer, and a branch point.

or comprising a sequence substantially complementary to the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30 , or comprising a nucleic acid sequence substantially complementary to one or more of the MSH3 nucleic acid sequences of any one of SEQ ID NOs: 13-18 and 31-42, and optionally
the RNA molecule comprises one or both of ssRNA and dsRNA;
the RNA molecule comprises an antisense oligonucleotide; and/or
each RNA molecule comprises 15-25 nucleotides in length;
22. The branched RNA compound of claim 21 .

each RNA molecule comprises a dsRNA comprising a sense strand and an antisense strand, each antisense strand independently comprising a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30; and optionally
the branched RNA compound comprises complementarity to at least 10, 11, 12, or 13 consecutive nucleotides of an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30;
each RNA molecule contains no more than three mismatches with the MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30; or
the branched RNA compound comprises substantially perfect complementarity to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30, and optionally
the antisense strand comprises a portion having the nucleic acid sequence of any one of SEQ ID NOs: 7 to 12; and/or
the antisense strand and/or the sense strand comprises a length of 15 to 25 nucleotides; and/or
the antisense strand is 20, 21 or 22 nucleotides in length; and/or
the sense strand is 15, 16, 18 or 20 nucleotides in length; and/or
The dsRNA comprises a double-stranded region of 15 to 20 base pairs; or comprises a double-stranded region of 15, 16, 18, or 20 base pairs.
23. A branched RNA compound according to claim 21 or 22 .

the dsRNA comprises blunt ends ; and/or
the dsRNA comprises at least one single-stranded nucleotide overhang, and optionally
the dsRNA comprises a single-stranded nucleotide overhang of 2 to 5 nucleotides;
A branched RNA compound according to any one of claims 21 to 23 .

the dsRNA comprises naturally occurring nucleotides, and/or
The dsRNA comprises at least one modified nucleotide, and optionally
the modified nucleotide comprises a 2'-O-methyl modified nucleotide, a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-deoxy modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-alkyl modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base containing nucleotide, and optionally
the dsRNA comprises at least 80% chemically modified nucleotides, the dsRNA is fully chemically modified, the dsRNA comprises at least 70% 2'-O-methyl nucleotide modifications, the antisense strand comprises at least 70% 2'-O-methyl nucleotide modifications, optionally the antisense strand comprises 70%-90% 2'-O-methyl nucleotide modifications and/or the sense strand comprises at least 65% 2'-O-methyl nucleotide modifications, optionally the sense strand comprises 100% 2'-O-methyl nucleotide modifications;
A branched RNA compound according to any one of claims 21 to 24 .

the dsRNA comprises at least one modified internucleotide linkage, and optionally
the modified internucleotide linkage comprises a phosphorothioate internucleotide linkage, and optionally
the branched RNA compound comprises 4 to 16 phosphorothioate internucleotide linkages, or comprises 8 to 13 phosphorothioate internucleotide linkages;
A branched RNA compound according to any one of claims 21 to 25 .

The branched RNA compound according to any one of claims 21 to 26 , wherein the dsRNA comprises at least one modified internucleotide linkage of formula (I):

(Wherein,
B is a base pair moiety;
W is selected from the group consisting of O, _OCH2 , OCH, _CH2 , and CH;
X is selected from the group consisting of halo, hydroxy, and C _1-6 alkoxy;
Y is selected from the group consisting of O ⁻ , OH, OR, NH ⁻ , NH ₂ , S ⁻ , and SH;
Z is selected from the group consisting of O and _CH2 ;
R is a protecting group;

is an optional double bond).

the sense strand comprises one or more nucleotide mismatches between the antisense strand and the sense strand, and optionally
the one or more nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand; or
the nucleotide mismatches are at positions 2, 6, and 12 from the 5' end of the sense strand;
A branched RNA compound according to any one of claims 23 to 27 .

the antisense strand comprises a 5' phosphate, a 5'-alkyl phosphonate, a 5' alkylene phosphonate, a 5' alkenyl phosphonate, or a mixture thereof, and optionally
the antisense strand comprises a 5' vinyl phosphonate;
A branched RNA compound according to any one of claims 23 to 28 .

The dsRNA comprises an antisense strand and a sense strand, each strand having a 5' end and a 3' end, wherein:
A:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand comprises alternating 2'-methoxy-ribonucleotides and 2'-fluoro-ribonucleotides;
(7) the nucleotides 1 to 2 from the 5' end of the sense strand are linked to each other via a phosphorothioate internucleotide linkage ;
B:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 70% 2'-O-methyl modifications;
(3) the nucleotide at position 14 from the 5' end of the antisense strand is not a 2'-methoxy-ribonucleotide;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 70% 2'-O-methyl modifications;
(7) the nucleotides 1 to 2 from the 5' end of the sense strand are linked to each other via a phosphorothioate internucleotide linkage;
C:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 85% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) the nucleotides 1 to 2 from the 5' end of the sense strand are linked to each other via a phosphorothioate internucleotide linkage;
D:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
E:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 4, 5, 6, and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains 100% 2'-O-methyl modifications;
(7) The nucleotides at positions 1 to 2 from the 5' end of the sense strand are linked to each other via phosphorothioate internucleotide linkages.
F:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2, 6, 14, and 16 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 65% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 9, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) the nucleotides 1 to 2 from the 5' end of the sense strand are linked to each other via a phosphorothioate internucleotide linkage;
or
G:
(1) the antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 1-6 and 19-30;
(2) the antisense strand contains at least 75% 2'-O-methyl modifications;
(3) the nucleotides at positions 2 and 14 from the 5' end of the antisense strand are not 2'-methoxy-ribonucleotides;
(4) the nucleotides at positions 1-2 through 1-7 from the 3' end of the antisense strand are linked to each other via phosphorothioate internucleotide linkages;
(5) a portion of the antisense strand is complementary to a portion of the sense strand;
(6) the sense strand contains at least 75% 2'-O-methyl modifications;
(7) the nucleotides at positions 7, 10, and 11 from the 3' end of the sense strand are not 2'-methoxy-ribonucleotides;
(8) the nucleotides 1 to 2 from the 5' end of the sense strand are linked to each other via a phosphorothioate internucleotide linkage;
22. A dsRNA according to claim 1 or a branched RNA compound according to claim 21 .

a functional moiety is linked to the 5'-end and/ or the 3'-end of the antisense strand;
functional moieties are linked to the 5' and 3' ends of the sense strand; or
a functional moiety is linked to the 3' end of the sense strand, and optionally
the functional moiety comprises a hydrophobic moiety, and optionally
the hydrophobic moiety is selected from the group consisting of fatty acids, steroids, secosteroids, lipids, gangliosides, nucleoside analogs, endocannabinoids, vitamins, and mixtures thereof; and optionally
the steroid is selected from the group consisting of cholesterol and lithocholic acid (LCA);
the fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosanoic acid (DCA);
The vitamin is selected from the group consisting of choline, vitamin A, vitamin E, derivatives thereof, and metabolites thereof; or
the vitamins are selected from the group consisting of retinoic acid and alpha-tocopherol succinate, and optionally
the functional moiety is linked to the antisense strand and/or the sense strand by a linker, and optionally
The linker comprises a bivalent or trivalent linker, and optionally
The bivalent or trivalent linker is

wherein n is 1, 2, 3, 4, or 5; or
the linker comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphodiester, a phosphorothioate, a phosphoramidate, an amide, a carbamate, or a combination thereof; or
If the linker is a trivalent linker, the linker further links a phosphodiester or phosphodiester derivative; or, optionally,
The phosphodiester or phosphodiester derivative is selected from the group consisting of:

(wherein X is O, S or _BH3 );
A branched RNA compound according to any one of claims 23 to 30 .

The branched RNA compound according to any one of claims 23 to 31, wherein the nucleotides at positions 1 and 2 from the 3' end of the sense strand and the nucleotides at positions 1 and 2 from the 5' end of the antisense strand are linked to adjacent ribonucleotides via phosphorothioate bonds.

Compounds of formula (I):

(Wherein:
L comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof; and formula (I) optionally comprises one or more branch points B, and one or more spacers S,
B is, independently at each occurrence, a polyvalent organic species or derivative thereof;
S, independently for each occurrence, comprises an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or a combination thereof;
N is a double-stranded nucleic acid comprising a sense strand and an antisense strand, the length of which is 15-35 bases; wherein the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30;
the sense strand and the antisense strand each independently comprise one or more chemical modifications;
n is 2, 3, 4, 5, 6, 7, or 8).

34. The compound of claim 33, wherein the compound has a structure selected from formulas (I-1) to (I-9):

; or
the antisense strand comprises a 5' end group R selected from the group consisting of:

or the compound has the structure of formula (II):

(Wherein,
X is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
Y is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
- represents a phosphodiester internucleoside linkage;
= represents a phosphorothioate internucleoside linkage;
--- independently represents a base pair interaction or a mismatch at each occurrence;
Structure of formula (IV):

(Wherein,
X is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
Y is independently selected at each occurrence from adenosine, guanosine, uridine, cytidine, and chemically modified derivatives thereof;
- represents a phosphodiester internucleoside linkage;
= represents a phosphorothioate internucleoside linkage;
--- represents, independently at each occurrence, a base pair interaction or a mismatch.
having
L is structure L1;

, optionally R is R3 ^and n is 2; and/or
L is structure L2;

Optionally, R is R3 ^and n is 2;
Compound.

A pharmaceutical composition for inhibiting the expression of the MSH3 gene in an organism, comprising a dsRNA according to any one of claims 1 to 12 and 30 or a compound according to any one of claims 21 to 34 , and optionally a pharma- ceutically acceptable carrier.
A pharmaceutical composition , wherein said dsRNA or compound inhibits said expression of said MSH3 gene by at least 50%, or by at least 80%.

A pharmaceutical composition for treating a neurodegenerative disease , comprising a compound according to any one of claims 21 to 34 , and optionally
The compound is formulated to be administered to the brain of a patient;
The compound is formulated to be administered by intracerebroventricular (ICV) injection, intrastriatal (IS) injection, intravenous (IV) injection, subcutaneous (SQ) injection, or a combination thereof; or
wherein the compound causes a decrease in the MSH3 gene mRNA in one or more of the hippocampus, striatum, cortex, cerebellum, thalamus, hypothalamus, and spinal cord of the patient, and optionally
A pharmaceutical composition, wherein said compound inhibits said expression of said MSH3 gene by at least 50%, or by at least 80%.

1. A method for reducing HTT mRNA in a cell in vitro , comprising:
(a) introducing into said cell an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence;
(b) maintaining the cells produced in step (a) for a time sufficient to obtain degradation of the HTT mRNA, thereby reducing HTT mRNA in the cells;
and optionally
the oligonucleotide comprises a double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand;
the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30, and optionally
The method of claim 1, wherein the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 13-18 and 31-42.

A pharmaceutical composition for treating or managing Huntington's disease (HD), comprising an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence, and optionally
the oligonucleotide comprises a double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand;
the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30, and optionally
The antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 13-18 and 31-42;
Pharmaceutical compositions .

1. A pharmaceutical composition for treating or managing a trinucleotide repeat disease or disorder, comprising an oligonucleotide comprising a sequence substantially complementary to an MSH3 nucleic acid sequence, and optionally
the oligonucleotide comprises a double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand;
the antisense strand comprises a sequence substantially complementary to an MSH3 nucleic acid sequence of any one of SEQ ID NOs: 1-6 and 19-30, and optionally
The antisense strand comprises a sequence substantially complementary to any one of the MSH3 nucleic acid sequences of SEQ ID NOs: 13-18 and 31-42;
Pharmaceutical Compositions

1. A pharmaceutical composition for treating or managing Huntington's disease (HD), comprising:
A pharmaceutical composition comprising a dsRNA according to any one of claims 1 to 12 and 30 , a vector according to any one of claims 78 to 82, a compound according to claim 16 or 17 , or a compound according to any one of claims 21 to 34 .

1. A pharmaceutical composition for treating or managing a trinucleotide repeat disease or disorder, comprising:
A pharmaceutical composition comprising a dsRNA according to any one of claims 1 to 12 and 30 , a vector according to any one of claims 78 to 82, a compound according to claim 16 or 17 , or a compound according to any one of claims 21 to 34 .