JPWO2020117702A5

JPWO2020117702A5 -

Info

Publication number: JPWO2020117702A5
Application number: JP2021553755A
Authority: JP
Publication date: 2022-12-09

Description

１つまたは複数の態様の詳細は、以下の説明に示される。他の特色、目的および利点は、説明および特許請求の範囲から明らかとなる。
特定の実施形態では、例えば、以下が提供される：
（項目１）
１０～３０の連結されたヌクレオシド長の一本鎖オリゴヌクレオチドであって、ＭＳＨ３遺伝子に対して少なくとも８０％の相補性を有する少なくとも１０個の連続する核酸塩基の領域を含む、オリゴヌクレオチド。
（項目２）
前記オリゴヌクレオチドが、
（ａ）連結されたデオキシリボヌクレオシドを含むＤＮＡコア配列；
（ｂ）連結されたヌクレオシドを含む５’隣接配列；および
（ｃ）連結されたヌクレオシドを含む３’隣接配列
を含み、
前記ＤＮＡコアが、ＭＳＨ３遺伝子に対して少なくとも８０％の相補性を有する少なくとも１０個の連続する核酸塩基の領域を含み、前記５’隣接配列と前記３’隣接配列との間に位置付けられ；前記５’隣接配列および前記３’隣接配列が各々、少なくとも２つの連結されたヌクレオシドを含み；各隣接配列の少なくとも１つのヌクレオシドが、代替えのヌクレオシドを含む、項目１に記載のオリゴヌクレオチド。
（項目３）
細胞におけるヒトＭＳＨ３遺伝子の発現を阻害するための１０～３０の連結されたヌクレオシド長の一本鎖オリゴヌクレオチドであって、ＭＳＨ３遺伝子に対して少なくとも８０％の相補性を有する少なくとも１０個の連続する核酸塩基の領域を含む、オリゴヌクレオチド。
（項目４）
前記オリゴヌクレオチドが、
（ａ）連結されたデオキシリボヌクレオシドを含むＤＮＡコア；
（ｂ）連結されたヌクレオシドを含む５’隣接配列；および
（ｃ）連結されたヌクレオシドを含む３’隣接配列
を含み、
前記ＤＮＡコアが、ＭＳＨ３遺伝子に対して少なくとも８０％の相補性を有する少なくとも１０個の連続する核酸塩基の領域を含み、前記５’隣接配列と前記３’隣接配列との間に位置付けられ；前記５’隣接配列および前記３’隣接配列が各々、少なくとも２つの連結されたヌクレオシドを含み；各隣接配列の少なくとも１つのヌクレオシドが、代替えのヌクレオシドを含む、項目３に記載のオリゴヌクレオチド。
（項目５）
少なくとも１０核酸塩基の前記領域が、ＭＳＨ３遺伝子に対して少なくとも９０％の相補性を有する、項目１から４のいずれか一項に記載のオリゴヌクレオチド。
（項目６）
少なくとも１０核酸塩基の前記領域が、ＭＳＨ３遺伝子に対して少なくとも９５％の相補性を有する、項目１から５のいずれか一項に記載のオリゴヌクレオチド。
（項目７）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の１５５～１９９、３５５～３８５、３９８～４９６、５５９～５８９、６７６～７２４、７６２～８１０、８７６～９０３、９１２～９７４、９８４～１０４７、１０５４～１０９８、１１１４～１１７９、１２００～１２２７、１２９４～１３３７、１３９２～１４１７、１４６７～１４９３、１５１７～１６３０、１６６５～１７４７、１７６８～１８６６、２０２９～２０６３、２０８７～２１９９、２２６２～２２９３、２３０４～２３３０、２３７１～２４１０、２４３２～２４５８、２４９４～２５２１、２５３９～２６４７、２６７９～２７１３、２７２７～２７５３、２７６７～２９２０、２９３３～３０００、３０４６～３０７３、３１３２３２４５、３２６６～３３０６、３３９７～３４８４、３５２８～３５７５、３５９１～３６１７、３７５３～３７９２、３９０１～３９３６、４０７４～４１０１または４２８１～４３１９位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目８）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の１５５～１９９、３５９～３８５、３９８～４９６、５５９～５８９、６７６～７２４、７６２～８１０、８７６～９７４、９８４～１０９８、１１１４～１１７９、１２００～１２２７、１２９４～１３３７、１３９２～１４１７、１４６７～１４９３、１５１７～１６３０、１６６５～１７４７、１８３４～１８６６、２０２９～２０５６、２０９３～２１９９、２２６２～２２９３、２３０４～２３２９、２３７１～２４１０、２４３３～２４５８、２４９４～２５２１、２５３９～２６４７、２６７９～２７１３、２７２７～２７５３、２７６７～２９２０、２９３３～３０００、３０４６～３０７２、３１３２～３２４５、３２６６～３３０３、３３９７～３４８４、３５２８～３５７５、３５９１～３６１７、３７５３～３７９２、３９０１～３９３６、４０７６～４１０１または４２８１～４３１９位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目９）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の１５５～１９６、３５９～３８５、４１３～４６２、５５９～５８９、６７６～７２４、７６２～８１０、８７６～９７４、９８４～１０９６、１１１４～１１７９、１２００～１２２７、１２９４～１３３７、１４６７～１４９３、１５１７～１６３０、１６６５～１７４７、１８３４～１８６６、２０２９～２０５６、２０９３～２１９９、２２６５～２２９３、２３７８～２４１０、２４３３～２４５８、２４９４～２５２１、２５３９～２６４７、２６７９～２７１２、２７２７～２７５３、２７６７～２９１９、２９３４～３０００、３０４６～３０７１、３１４４～３１８３、３２２０～３２４５、３３９７～３４８４、３５３４～３５７５、３５９１～３６１６、３９０１～３９３１または４２８１～４３０６位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１０）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の４３５～４６２、５５９～５８４、７６３～８０８、８７６～９０２、９３１～９５８、１００１～１０８３、１１１４～１１７９、１２９４～１３３７、１５４４～１５７８、１８３５～１８６３、２０３１～２０５６、２１４４～２１６９、２５４３～２５７７、２５９０～２６１５、２６２１～２６４７、２６８５～２７１１、２７６９～２７９５または２８１６～２８６８位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１１）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の８７６～９０２、９３０～９５８、１０５６～１０８１、１１１４～１１３９、１１５４～１１７９、１３１０～１３３７、１５４６～１５７１、１８３６～１８６２、２１４１～２１９９、２２６７～２２９２、２５４０～２５８０、２６２０～２６４７、２６８６～２７１１、２７６９～２８６８、２９３９～２９７６、３１４４～３１６９または３３９９～３４２４位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１２）
少なくとも１０核酸塩基の前記領域が、参照ｍＲＮＡＮＭ＿００２４３９．４の配列に対応するＭＳＨ３遺伝子に対して、前記ＭＳＨ３遺伝子の９８４～１０２１、１４６７～１４９３、１７２２～１７４７、１７６７～１８０２、１８３３～１８６１、２３８５～２４１０、２５５４～２５８１、２８１６～２８４５、２８６１～２９２０または３１５１～３１８３位のうち１つまたは複数の位置において相補的である、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１３）
配列番号６～２５４５のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１４）
配列番号２０、２２～２９、３１～３２、７７～７８、８１～８２、１１５、１１７、１３０、１３２～１３４、１４４～１４５、１４７、１６７～１６８、２１０、２１２～２１５、２９０～２９３、２９５～２９６、２９９～３０５、３０９、３５１～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４５９～４６０、４７９、４８２～４９３、４９７～４９８、５００～５０１、５０３～５１２、５４３～５５０、５５２～５６０、５６２、５８２～５８５、５８８～５９１、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７２４～７２５、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５２、８５６、８８３～８８５、８８９、８９３～８９７、９３６、９４０～９４１、９４５、９４８、９５０、９５５、９５９～９６１、９６５～９６８、９７２～９７３、９９９、１００７、１０１６～１０１７、１０１９、１０２１～１０２２、１０３６、１０４０～１０４５、１０４７、１１７０、１１７２～１１７３、１２１１、１２１６、１２２２、１２３５、１２４０～１２４２、１２４４～１２４９、１２５１～１２５２、１２５４～１２５９、１２６８、１３１６、１３１８～１３２２、１３２８～１３２９、１３７３～１３７５、１３７９～１３８３、１３８６～１３８７、１４０７～１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４１、１５６５～１５６６、１５７９、１５８１～１５８９、１５９１、１６００～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３９、１６４３、１６５０～１６６０、１６６３～１６６５、１６６８～１６７５、１７１３～１７１４、１７１６～１７２２、１７２４、１７２７～１７３１、１７４１、１７４５～１７４７、１７５１～１７５５、１７９９～１８０１、１８５９～１８６６、１８６８～１８６９、１８９４～１８９６、１９０５～１９０８、１９５４、１９６４～１９６６、１９６９、２０６６～２０７０、２０７５～２０７９、２１０８、２１３８、２１４３～２１４７、２１５７～２１６０、２１９３～２１９４、２２９９～２３００、２３１２～２３１３、２３８５、２３８８、２３９０～２３９５、２４１６～２４１８、２４６０、２４６２または２４６３のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１５）
配列番号２０、２２、２５～２９、３１～３２、８１～８２、１１５、１３０、１３２～１３４、１４４、１４５、１４７、１６８、２１０、２１２～２１５、２９０～２９３、２９５～２９６、２９９～３０５、３０９、３５１～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４５９～４６０、４７９、４８２～４９３、４９７～４９８、５００～５０１、５０３～５０６、５０８～５１２、５４３～５５０、５５２～５６０、５６２、５８２～５８５、５８９～５９１、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７２４、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５２、８５６、８８３～８８５、８８９、８９３～８９７、９３６、９４０～９４１、９４５、９４８、９５０、９５５、９５９～９６１、９６５～９６８、９７２～９７３、１０４１～１０４５、１０４７、１１７０、１１７２、１２１６、１２２２、１２３５、１２４１～１２４２、１２４４～１２４９、１２５１～１２５２、１２５４～１２５９、１２６８、１３１６、１３１８～１３１９、１３２１～１３２２、１３２８、１３７３、１３７９～１３８３、１３８６～１３８７、１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４１、１５６５～１５６６、１５７９、１５８１～１５８２、１５８４～１５８９、１５９１、１６０１～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３８、１６５０～１６５５、１６５９、１６６５、１６６８～１６７５、１７１３～１７１４、１７１６～１７２２、１７２７～１７３１、１７４５、１７４７、１７５１～１７５５、１７９９～１８００、１８５９、１８６１～１８６２、１８６５～１８６６、１８６８～１８６９、１８９５～１８９６、１９０５～１９０８、１９５４、１６９４～１９６６、２０６６～２０７０、２０７５～２０７９、２１０８、２１３８、２１４４～２１４６、２１５８～２１６０、２１９３～２１９４、２２９９、２３００、２３１３、２３８５、２３８８、２３９０～２３９２、２３９４～２３９５、２４１８、２４６０または２４６２～２４６３のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１６）
配列番号２０、２５～２９、３２、８１～８２、１３０、１３３～１３４、１４４～１４５、１４７、２１０、２１２～２１３、２１５、２９０～２９３、２９５～２９６、２９９～３０４、３０９、３５１、３５２～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４６０、４７９、４８２～４８６、４８８～４９２、４９７～４９８、５００～５０１、５０３～５０６、５０８～５１２、５４４～５５０、５５３～５５８、５６０、５８２～５８５、５８９、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５１、８５６、８８３、８８５、８８９、８９３、８９５～８９７、９３６、９４０、９４５、９６１、９６５～９６８、９７２～９７３、１０４１～１０４５、１０４７、１１７０、１１７２、１２１６、１２２２、１２３５、１２４４、１２４６～１２４９、１２５１～１２５２、１２５４～１２５５、１２５７～１２５９、１２６８、１３１９、１３２１～１３２２、１３８０～１３８１、１３８６～１３８７、１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４０、１５６５～１５６６、１５７９、１５８１～１５８２、１５８４～１５８９、１５９１、１６０１～１６０４、１６０６～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３８、１６５１～１６５４、１６６８、１６７０～１６７４、１７１４、１７１７～１７２２、１７２７～１７３１、１７４５、１７５１～１７５５、１７９９、１８６１、１８６９、１９０８、１９６４、１９６６、２０６６～２０６９、２０７５～２０７６、２０７８～２０７９、２１０８、２１４４～２１４５、２１５８～２１６０、２１９３、２３８５、２３９０または２４６０のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１７）
配列番号１４５、１４７、２１０、３５２、３６５、３６６、４０７、４０８、４３９～４４２、４４４、４９２、５００、５０４、５１１、５１２、５４４～５４７、５８２、６０４、６１６、６９９、７００、７０２、７０５～７０７、８３９～８４２、８４８、１０４２～１０４５、１１７２、１２５５、１４５４～１４５７、１４７７～１４９９、１５３８、１５３９、１５８１、１５８２、１６０６、１６０７、１６１０または１６３１～１６３３のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１８）
配列番号４０７、４０８、４４１、４４２、４４４、５４５、５８２、６１６、７０５～７０７、８４１、１０４３、１０４４、１２５２、１２５５、１２６８、１３２１、１４５１、１４５４～１４６０、１４９７～１４９９、１５３８、１５３９、１５８１、１５８２、１５８７、１６０１、１６０２、１６０６、１６０７、１６１０、１６３１～１６３３、１７１９、１７２１、１７３０、１７３１、１８６１または２０６８のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目１９）
配列番号４７９、４８２～４９１、７７０、７７１、９７３、９９８～１０００、１００７、１００８、１０４０～１０４３、１３８７、１４５４、１４５６、１４５９～１４６１、１５３８、１５３９、１６０６、１６０７、１６１０、１６４３～１６６５、１６６８～１６７５または１８６２～１８６９のうちいずれか１つの核酸塩基配列を含む、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２０）
前記オリゴヌクレオチドの前記核酸塩基配列が、配列番号６～２５４５のうちいずれか１つからなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２１）
配列番号２０、２２～２９、３１～３２、７７～７８、８１～８２、１１５、１１７、１３０、１３２～１３４、１４４～１４５、１４７、１６７～１６８、２１０、２１２～２１５、２９０～２９３、２９５～２９６、２９９～３０５、３０９、３５１～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４５９～４６０、４７９、４８２～４９３、４９７～４９８、５００～５０１、５０３～５１２、５４３～５５０、５５２～５６０、５６２、５８２～５８５、５８８～５９１、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７２４～７２５、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５２、８５６、８８３～８８５、８８９、８９３～８９７、９３６、９４０～９４１、９４５、９４８、９５０、９５５、９５９～９６１、９６５～９６８、９７２～９７３、９９９、１００７、１０１６～１０１７、１０１９、１０２１～１０２２、１０３６、１０４０～１０４５、１０４７、１１７０、１１７２～１１７３、１２１１、１２１６、１２２２、１２３５、１２４０～１２４２、１２４４～１２４９、１２５１～１２５２、１２５４～１２５９、１２６８、１３１６、１３１８～１３２２、１３２８～１３２９、１３７３～１３７５、１３７９～１３８３、１３８６～１３８７、１４０７～１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４１、１５６５～１５６６、１５７９、１５８１～１５８９、１５９１、１６００～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３９、１６４３、１６５０～１６６０、１６６３～１６６５、１６６８～１６７５、１７１３～１７１４、１７１６～１７２２、１７２４、１７２７～１７３１、１７４１、１７４５～１７４７、１７５１～１７５５、１７９９～１８０１、１８５９～１８６６、１８６８～１８６９、１８９４～１８９６、１９０５～１９０８、１９５４、１９６４～１９６６、１９６９、２０６６～２０７０、２０７５～２０７９、２１０８、２１３８、２１４３～２１４７、２１５７～２１６０、２１９３～２１９４、２２９９～２３００、２３１２～２３１３、２３８５、２３８８、２３９０～２３９５、２４１６～２４１８、２４６０、２４６２または２４６３のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２２）
配列番号２０、２２、２５～２９、３１～３２、８１～８２、１１５、１３０、１３２～１３４、１４４、１４５、１４７、１６８、２１０、２１２～２１５、２９０～２９３、２９５～２９６、２９９～３０５、３０９、３５１～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４５９～４６０、４７９、４８２～４９３、４９７～４９８、５００～５０１、５０３～５０６、５０８～５１２、５４３～５５０、５５２～５６０、５６２、５８２～５８５、５８９～５９１、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７２４、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５２、８５６、８８３～８８５、８８９、８９３～８９７、９３６、９４０～９４１、９４５、９４８、９５０、９５５、９５９～９６１、９６５～９６８、９７２～９７３、１０４１～１０４５、１０４７、１１７０、１１７２、１２１６、１２２２、１２３５、１２４１～１２４２、１２４４～１２４９、１２５１～１２５２、１２５４～１２５９、１２６８、１３１６、１３１８～１３１９、１３２１～１３２２、１３２８、１３７３、１３７９～１３８３、１３８６～１３８７、１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４１、１５６５～１５６６、１５７９、１５８１～１５８２、１５８４～１５８９、１５９１、１６０１～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３８、１６５０～１６５５、１６５９、１６６５、１６６８～１６７５、１７１３～１７１４、１７１６～１７２２、１７２７～１７３１、１７４５、１７４７、１７５１～１７５５、１７９９～１８００、１８５９、１８６１～１８６２、１８６５～１８６６、１８６８～１８６９、１８９５～１８９６、１９０５～１９０８、１９５４、１６９４～１９６６、２０６６～２０７０、２０７５～２０７９、２１０８、２１３８、２１４４～２１４６、２１５８～２１６０、２１９３～２１９４、２２９９、２３００、２３１３、２３８５、２３８８、２３９０～２３９２、２３９４～２３９５、２４１８、２４６０または２４６２～２４６３のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２３）
配列番号２０、２５～２９、３２、８１～８２、１３０、１３３～１３４、１４４～１４５、１４７、２１０、２１２～２１３、２１５、２９０～２９３、２９５～２９６、２９９～３０４、３０９、３５１、３５２～３５９、３６１～３６２、３６５～３６６、３６８、４０７～４０９、４３２、４３７～４４２、４４４、４６０、４７９、４８２～４８６、４８８～４９２、４９７～４９８、５００～５０１、５０３～５０６、５０８～５１２、５４４～５５０、５５３～５５８、５６０、５８２～５８５、５８９、６０３～６０４、６１１、６１３～６１６、６５９、６６１、６９９～７００、７０２、７０５～７０７、７７０～７７１、８１２～８１６、８３８～８４２、８４５～８５１、８５６、８８３、８８５、８８９、８９３、８９５～８９７、９３６、９４０、９４５、９６１、９６５～９６８、９７２～９７３、１０４１～１０４５、１０４７、１１７０、１１７２、１２１６、１２２２、１２３５、１２４４、１２４６～１２４９、１２５１～１２５２、１２５４～１２５５、１２５７～１２５９、１２６８、１３１９、１３２１～１３２２、１３８０～１３８１、１３８６～１３８７、１４０８、１４３３～１４３５、１４５０～１４５１、１４５４～１４６１、１４７６～１４７７、１４９６～１４９９、１５３２、１５３８～１５４０、１５６５～１５６６、１５７９、１５８１～１５８２、１５８４～１５８９、１５９１、１６０１～１６０４、１６０６～１６０７、１６１０、１６２５、１６２７～１６２９、１６３１～１６３８、１６５１～１６５４、１６６８、１６７０～１６７４、１７１４、１７１７～１７２２、１７２７～１７３１、１７４５、１７５１～１７５５、１７９９、１８６１、１８６９、１９０８、１９６４、１９６６、２０６６～２０６９、２０７５～２０７６、２０７８～２０７９、２１０８、２１４４～２１４５、２１５８～２１６０、２１９３、２３８５、２３９０または２４６０のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２４）
配列番号１４５、１４７、２１０、３５２、３６５、３６６、４０７、４０８、４３９～４４２、４４４、４９２、５００、５０４、５１１、５１２、５４４～５４７、５８２、６０４、６１６、６９９、７００、７０２、７０５～７０７、８３９～８４２、８４８、１０４２～１０４５、１１７２、１２５５、１４５４～１４５７、１４７７～１４９９、１５３８、１５３９、１５８１、１５８２、１６０６、１６０７、１６１０または１６３１～１６３３のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２５）
配列番号４０７、４０８、４４１、４４２、４４４、５４５、５８２、６１６、７０５～７０７、８４１、１０４３、１０４４、１２５２、１２５５、１２６８、１３２１、１４５１、１４５４～１４６０、１４９７～１４９９、１５３８、１５３９、１５８１、１５８２、１５８７、１６０１、１６０２、１６０６、１６０７、１６１０、１６３１～１６３３、１７１９、１７２１、１７３０、１７３１、１８６１または２０６８のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２６）
配列番号４７９、４８２～４９１、７７０、７７１、９７３、９９８～１０００、１００７、１００８、１０４０～１０４３、１３８７、１４５４、１４５６、１４５９～１４６１、１５３８、１５３９、１６０６、１６０７、１６１０、１６４３～１６６５、１６６８～１６７５または１８６２～１８６９のうちいずれか１つの核酸塩基配列からなる、項目１から６のいずれか一項に記載のオリゴヌクレオチド。
（項目２７）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２０ｎＭのオリゴヌクレオチド濃度において、少なくとも５０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目２８）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２０ｎＭのオリゴヌクレオチド濃度において、少なくとも６０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目２９）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２０ｎＭのオリゴヌクレオチド濃度において、少なくとも７０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３０）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２０ｎＭのオリゴヌクレオチド濃度において、少なくとも８５％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３１）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２ｎＭにおいて、少なくとも５０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３２）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２ｎＭのオリゴヌクレオチド濃度において、少なくとも６０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３３）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２ｎＭのオリゴヌクレオチド濃度において、少なくとも７０％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３４）
細胞アッセイを使用して決定した場合、対照細胞と比較した場合に、２ｎＭのオリゴヌクレオチド濃度において、少なくとも８５％のｍＲＮＡ阻害を示す、項目１から２６のいずれか一項に記載のオリゴヌクレオチド。
（項目３５）
少なくとも１つの代替えのヌクレオシド間連結を含む、項目１から３４のいずれか一項に記載のオリゴヌクレオチド。
（項目３６）
前記少なくとも１つの代替えのヌクレオシド間連結が、ホスホロチオエートヌクレオシド間連結である、項目３５に記載のオリゴヌクレオチド。
（項目３７）
前記少なくとも１つの代替えのヌクレオシド間連結が、２’－アルコキシヌクレオシド間連結である、項目３５に記載のオリゴヌクレオチド。
（項目３８）
前記少なくとも１つの代替えのヌクレオシド間連結が、アルキルホスフェートヌクレオシド間連結である、項目３５に記載のオリゴヌクレオチド。
（項目３９）
少なくとも１つの代替えの核酸塩基を含む、項目１から３８のいずれか一項に記載のオリゴヌクレオチド。
（項目４０）
前記代替えの核酸塩基が、５’－メチルシトシン、プソイドウリジンまたは５－メトキシウリジンである、項目３９に記載のオリゴヌクレオチド。
（項目４１）
少なくとも１つの代替えの糖部分を含む、項目１から４０のいずれか一項に記載の改変されたオリゴヌクレオチド。
（項目４２）
前記代替えの糖部分が、２’－ＯＭｅまたは二環式核酸である、項目４１に記載の改変されたオリゴヌクレオチド。
（項目４３）
一価または分岐鎖二価もしくは三価リンカーを介して前記オリゴヌクレオチドの５’末端または３’末端にコンジュゲートされたリガンドをさらに含む、項目１から４２のいずれか一項に記載のオリゴヌクレオチド。
（項目４４）
ＭＳＨ３遺伝子の少なくとも１７個の連続するヌクレオチドに対して相補的な領域を含む、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目４５）
ＭＳＨ３遺伝子の少なくとも１９個の連続するヌクレオチドに対して相補的な領域を含む、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目４６）
ＭＳＨ３遺伝子の１９～２３個の連続するヌクレオチドに対して相補的な領域を含む、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目４７）
ＭＳＨ３遺伝子の１９個の連続するヌクレオチドに対して相補的な領域を含む、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目４８）
ＭＳＨ３遺伝子の２０個の連続するヌクレオチドに対して相補的な領域を含む、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目４９）
約１５～２５ヌクレオシド長である、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目５０）
２０ヌクレオシド長である、項目１から４３のいずれか一項に記載のオリゴヌクレオチド。
（項目５１）
項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つまたは複数および薬学的に許容される担体または賦形剤を含む医薬組成物。
（項目５２）
項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つまたは複数および脂質ナノ粒子、ポリプレックスナノ粒子、リポプレックスナノ粒子またはリポソームを含む組成物。
（項目５３）
細胞においてＭＳＨ３の転写を阻害する方法であって、前記細胞を、ＭＳＨ３遺伝子のｍＲＮＡ転写物の分解を得るために十分な時間にわたって、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物と接触させて、前記細胞において前記ＭＳＨ３遺伝子の発現を阻害するステップを含む、方法。
（項目５４）
トリヌクレオチドリピート伸長障害の処置、予防またはその進行の遅延を必要とする対象においてトリヌクレオチドリピート伸長障害を処置、予防するまたはその進行を遅延させる方法であって、前記対象に、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物を投与するステップを含む、方法。
（項目５５）
トリヌクレオチドリピート伸長障害を有すると識別された対象の細胞においてＭＳＨ３のレベルおよび／または活性を低減させる方法であって、前記細胞を、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物と接触させるステップを含む、方法。
（項目５６）
細胞においてＭＳＨ３遺伝子の発現を阻害するための方法であって、前記細胞を、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物と接触させるステップ、およびＭＳＨ３遺伝子のｍＲＮＡ転写物の分解を得るために十分な時間にわたって、前記細胞を維持し、それによって、前記細胞において前記ＭＳＨ３遺伝子の発現を阻害するステップを含む、方法。
（項目５７）
細胞においてトリヌクレオチドリピート伸長を減少させる方法であって、前記細胞を、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物と接触させるステップを含む、方法。
（項目５８）
前記細胞が対象中にある、項目５６または５７に記載の方法。
（項目５９）
前記対象がヒトである、項目５４、５５および５８のいずれか一項に記載の方法。
（項目６０）
前記細胞が、中枢神経系の細胞または筋肉細胞である、項目５４から５８のいずれか一項に記載の方法。
（項目６１）
前記対象が、トリヌクレオチドリピート伸長障害を有すると識別されている、項目５４、５５および５８から６０のいずれか一項に記載の方法。
（項目６２）
前記トリヌクレオチドリピート伸長障害が、ポリグルタミン病である、項目５４、５５および５７から６１のいずれか一項に記載の方法。
（項目６３）
前記ポリグルタミン病が、歯状核赤核淡蒼球ルイ体萎縮症、ハンチントン病、球脊髄性筋萎縮症、脊髄小脳失調症１型、脊髄小脳失調症２型、脊髄小脳失調症３型、脊髄小脳失調症６型、脊髄小脳失調症７型、脊髄小脳失調症１７型およびハンチントン病様２からなる群から選択される、項目６２に記載の方法。
（項目６４）
前記トリヌクレオチドリピート伸長障害が、非ポリグルタミン病である、項目５４から６１のいずれか一項に記載の方法。
（項目６５）
前記非ポリグルタミン病が、脆弱Ｘ症候群、脆弱Ｘ関連振戦／失調症候群、脆弱ＸＥ精神遅滞、フリードライヒ運動失調症、筋強直性ジストロフィー１型、脊髄小脳失調症８型、脊髄小脳失調症１２型、眼咽頭型筋ジストロフィー、脆弱Ｘ関連早期卵巣機能不全、ＦＲＡ２Ａ症候群、ＦＲＡ７Ａ症候群および早期乳児てんかん性脳症からなる群から選択される、項目６４に記載の方法。
（項目６６）
トリヌクレオチドリピート伸長障害の予防または処置における使用のための、項目１から５０のいずれか一項に記載の１つもしくは複数のオリゴヌクレオチド、項目５１に記載の医薬組成物または項目５２に記載の組成物。
（項目６７）
前記トリヌクレオチドリピート伸長障害が、歯状核赤核淡蒼球ルイ体萎縮症、ハンチントン病、球脊髄性筋萎縮症、脊髄小脳失調症１型、脊髄小脳失調症２型、脊髄小脳失調症３型、脊髄小脳失調症６型、脊髄小脳失調症７型、脊髄小脳失調症１７型、ハンチントン病様２、脆弱Ｘ症候群、脆弱Ｘ関連振戦／失調症候群、脆弱ＸＥ精神遅滞、フリードライヒ運動失調症、筋強直性ジストロフィー１型、脊髄小脳失調症８型、脊髄小脳失調症１２型、眼咽頭型筋ジストロフィー、脆弱Ｘ関連早期卵巣機能不全、ＦＲＡ２Ａ症候群、ＦＲＡ７Ａ症候群および早期乳児てんかん性脳症からなる群から選択される、項目６８に記載の使用のためのオリゴヌクレオチド、医薬組成物または組成物。
（項目６８）
前記トリヌクレオチドリピート伸長障害が、ハンチントン病である、項目６６または６７に記載の使用のためのオリゴヌクレオチド、医薬組成物または組成物。
（項目６９）
前記トリヌクレオチドリピート伸長障害が、フリードライヒ運動失調症である、項目６６または６７に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目７０）
前記トリヌクレオチドリピート伸長障害が、筋強直性ジストロフィー１型である、項目６６または６７に記載の使用のためのオリゴヌクレオチド、医薬組成物または組成物。
（項目７１）
前記改変されたオリゴヌクレオチド、医薬組成物または組成物が、くも膜下腔内投与される、項目６６から７０のいずれか一項に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目７２）
前記改変されたオリゴヌクレオチド、医薬組成物または組成物が、脳室内投与される、項目６６から７０のいずれか一項に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目７３）
筋肉内投与される、項目６６から７０のいずれか一項に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目７４）
障害の処置、予防またはその進行の遅延を必要とする対象において障害を処置、予防するまたはその進行を遅延させる方法であって、前記対象が、トリヌクレオチドリピート伸長障害を患っており、前記対象に、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物を投与するステップを含む、方法。
（項目７５）
さらなる治療剤を投与するステップをさらに含む、項目７４に記載の方法。
（項目７６）
前記さらなる治療剤が、ハンチンチン遺伝子をコードするｍＲＮＡにハイブリダイズする別のオリゴヌクレオチドである、項目７５に記載の方法。
（項目７７）
対象においてトリヌクレオチドリピート伸長障害を予防するまたはその進行を遅延させる方法であって、前記対象に、前記対象のトリヌクレオチドリピート伸長障害の進行を遅延させるのに有効な量で、項目１から５０のいずれか一項に記載のオリゴヌクレオチドのうち１つもしくは複数、項目５１に記載の医薬組成物または項目５２に記載の組成物を投与するステップを含む、方法。
（項目７８）
前記トリヌクレオチドリピート伸長障害が、歯状核赤核淡蒼球ルイ体萎縮症、ハンチントン病、球脊髄性筋萎縮症、脊髄小脳失調症１型、脊髄小脳失調症２型、脊髄小脳失調症３型、脊髄小脳失調症６型、脊髄小脳失調症７型、脊髄小脳失調症１７型、ハンチントン病様２、脆弱Ｘ症候群、脆弱Ｘ関連振戦／失調症候群、脆弱ＸＥ精神遅滞、フリードライヒ運動失調症、筋強直性ジストロフィー１型、脊髄小脳失調症８型、脊髄小脳失調症１２型、眼咽頭型筋ジストロフィー、脆弱Ｘ関連早期卵巣機能不全、ＦＲＡ２Ａ症候群、ＦＲＡ７Ａ症候群および早期乳児てんかん性脳症からなる群から選択される、項目７７に記載の方法。
（項目７９）
前記トリヌクレオチドリピート伸長障害が、ハンチントン病である、項目７７または７８に記載の方法。
（項目８０）
前記トリヌクレオチドリピート伸長障害が、フリードライヒ運動失調症である、項目７７または７８に記載の方法。
（項目８１）
前記トリヌクレオチドリピート伸長障害が、筋強直性ジストロフィー１型である、項目７７または７８に記載の方法。
（項目８２）
さらなる治療剤を投与するステップをさらに含む、項目７７または７８に記載の方法。
（項目８３）
前記さらなる治療剤が、ハンチンチン遺伝子をコードするｍＲＮＡにハイブリダイズするオリゴヌクレオチドである、項目８２に記載の方法。
（項目８４）
前記トリヌクレオチドリピート伸長障害の進行が、予測された進行と比較した場合に、少なくとも１２０日、例えば、少なくとも６ヶ月、少なくとも１２ヶ月、少なくとも２年、少なくとも３年、少なくとも４年、少なくとも５年、少なくとも１０年またはそれよりも長く遅延される、項目７７から８３のいずれか一項に記載の方法。
（項目８５）
対象においてトリヌクレオチドリピート伸長障害を予防するまたはその進行を遅延させる際の使用のための、項目１から５０のいずれか一項に記載の１つもしくは複数のオリゴヌクレオチド、項目５１に記載の医薬組成物または項目５２に記載の組成物。
（項目８６）
前記トリヌクレオチドリピート伸長障害が、歯状核赤核淡蒼球ルイ体萎縮症、ハンチントン病、球脊髄性筋萎縮症、脊髄小脳失調症１型、脊髄小脳失調症２型、脊髄小脳失調症３型、脊髄小脳失調症６型、脊髄小脳失調症７型、脊髄小脳失調症１７型、ハンチントン病様２、脆弱Ｘ症候群、脆弱Ｘ関連振戦／失調症候群、脆弱ＸＥ精神遅滞、フリードライヒ運動失調症、筋強直性ジストロフィー１型、脊髄小脳失調症８型、脊髄小脳失調症１２型、眼咽頭型筋ジストロフィー、脆弱Ｘ関連早期卵巣機能不全、ＦＲＡ２Ａ症候群、ＦＲＡ７Ａ症候群および早期乳児てんかん性脳症からなる群から選択される、項目８５に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目８７）
前記トリヌクレオチドリピート伸長障害が、ハンチントン病である、項目８５または８６に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目８８）
前記トリヌクレオチドリピート伸長障害が、フリードライヒ運動失調症である、項目８５または８６に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目８９）
前記トリヌクレオチドリピート伸長障害が、筋強直性ジストロフィー１型である、項目８５または８６に記載のオリゴヌクレオチド、医薬組成物または組成物。
（項目９０）
前記トリヌクレオチドリピート伸長障害の進行が、予測された進行と比較した場合に、少なくとも１２０日、例えば、少なくとも６ヶ月、少なくとも１２ヶ月、少なくとも２年、少なくとも３年、少なくとも４年、少なくとも５年、少なくとも１０年またはそれよりも長く遅延される、項目８５から８９のいずれか一項に記載のオリゴヌクレオチド、医薬組成物または組成物。 The details of one or more aspects are set forth in the description below. Other features, objects and advantages will become apparent from the description and claims.
In certain embodiments, for example, the following are provided:
(Item 1)
A single-stranded oligonucleotide 10-30 linked nucleosides in length, said oligonucleotide comprising a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene.
(Item 2)
The oligonucleotide is
(a) a DNA core sequence comprising linked deoxyribonucleosides;
(b) a 5' flanking sequence comprising linked nucleosides; and
(c) a 3'flanking sequence comprising linked nucleosides
including
said DNA core comprises a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene and is positioned between said 5' flanking sequence and said 3' flanking sequence; The oligonucleotide of item 1, wherein the 5' flanking sequence and said 3' flanking sequence each comprise at least two linked nucleosides; at least one nucleoside of each flanking sequence comprises an alternative nucleoside.
(Item 3)
A single-stranded oligonucleotide 10-30 linked nucleosides long for inhibiting the expression of the human MSH3 gene in a cell, comprising at least 10 contiguous oligonucleotides having at least 80% complementarity to the MSH3 gene. An oligonucleotide comprising a region of nucleobases.
(Item 4)
The oligonucleotide is
(a) a DNA core comprising linked deoxyribonucleosides;
(b) a 5' flanking sequence comprising linked nucleosides; and
(c) a 3'flanking sequence comprising linked nucleosides
including
said DNA core comprises a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene and is positioned between said 5' flanking sequence and said 3' flanking sequence; 4. The oligonucleotide of item 3, wherein the 5' flanking sequence and said 3' flanking sequence each comprise at least two linked nucleosides; at least one nucleoside of each flanking sequence comprises an alternative nucleoside.
(Item 5)
5. The oligonucleotide of any one of items 1-4, wherein said region of at least 10 nucleobases has at least 90% complementarity to the MSH3 gene.
(Item 6)
6. The oligonucleotide of any one of items 1-5, wherein said region of at least 10 nucleobases has at least 95% complementarity to the MSH3 gene.
(Item 7)
155-199, 355-385, 398-496, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~903, 912~974, 984~1047, 1054~1098, 1114~1179, 1200~1227, 1294~1337, 1392~1417, 1467~1493, 1517~1630, 1665~1747, 1768~1866 ,2029-2063,2087-2199,2262-2293,2304-2330,2371-2410,2432-2458,2494-2521,2539-2647,2679-2713,2727-2753,2767-2920,2933-3000,3046 complementary at one or more of positions -3073, 31323245, 3266-3306, 3397-3484, 3528-3575, 3591-3617, 3753-3792, 3901-3936, 4074-4101 or 4281-4319 , items 1 to 6.
(Item 8)
155-199, 359-385, 398-496, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~974, 984~1098, 1114~1179, 1200~1227, 1294~1337, 1392~1417, 1467~1493, 1517~1630, 1665~1747, 1834~1866, 2029~2056, 2093~2199 ,2262-2293,2304-2329,2371-2410,2433-2458,2494-2521,2539-2647,2679-2713,2727-2753,2767-2920,2933-3000,3046-3072,3132-3245,3266 of items 1 to 6, which are complementary at one or more of positions -3303, 3397-3484, 3528-3575, 3591-3617, 3753-3792, 3901-3936, 4076-4101 or 4281-4319 Oligonucleotide according to any one of clauses.
(Item 9)
155-196, 359-385, 413-462, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~974, 984~1096, 1114~1179, 1200~1227, 1294~1337, 1467~1493, 1517~1630, 1665~1747, 1834~1866, 2029~2056, 2093~2199, 2265~2293 ,2378-2410,2433-2458,2494-2521,2539-2647,2679-2712,2727-2753,2767-2919,2934-3000,3046-3071,3144-3183,3220-3245,3397-3484,3534 7. The oligonucleotide of any one of items 1 to 6, which is complementary at one or more of positions -3575, 3591-3616, 3901-3931 or 4281-4306.
(Item 10)
435-462, 559-584, 763-808, 876-902, 931-958, 1001 of said MSH3 gene for said MSH3 gene wherein said region of at least 10 nucleobases corresponds to the sequence of reference mRNA NM_002439.4 ~1083, 1114-1179, 1294-1337, 1544-1578, 1835-1863, 2031-2056, 2144-2169, 2543-2577, 2590-2615, 2621-2647, 2685-2711, 2769-2795 or 2816-2868 7. The oligonucleotide of any one of items 1-6, which is complementary at one or more of the positions.
(Item 11)
876-902, 930-958, 1056-1081, 1114-1139, 1154-1179, 1310 of said MSH3 gene for said MSH3 gene wherein said region of at least 10 nucleobases corresponds to the sequence of reference mRNA NM_002439.4 1 of -1337, 1546-1571, 1836-1862, 2141-2199, 2267-2292, 2540-2580, 2620-2647, 2686-2711, 2769-2868, 2939-2976, 3144-3169 or 3399-3424 7. The oligonucleotide of any one of items 1-6, which is complementary at one or more positions.
(Item 12)
984-1021, 1467-1493, 1722-1747, 1767-1802, 1833-1861, 2385 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 7. The oligonucleotide of any one of items 1 to 6, wherein the oligonucleotide is complementary at one or more of positions -2410, 2554-2581, 2816-2845, 2861-2920 or 3151-3183.
(Item 13)
7. The oligonucleotide of any one of items 1-6, comprising the nucleobase sequence of any one of SEQ ID NOs: 6-2545.
(Item 14)
SEQ. 295-296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500-501, 503-512, 543-550, 552-560, 562, 582-585, 588-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 724-725, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961, 965-968, 972-973, 999, 1007, 1016-1017, 1019, 1021-1022, 1036, 1040-1045, 1047, 1170, 1172-1173, 1211, 1216, 1222, 1235, 1240-1242, 1244- 1249,1251-1252,1254-1259,1268,1316,1318-1322,1328-1329,1373-1375,1379-1383,1386-1387,1407-1408,1433-1435,1450-1451,1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581-1589, 1591, 1600-1607, 1610, 1625, 1627-1629, 1631-1639, 1643, 1650-1660, 1663- 1665,1668-1675,1713-1714,1716-1722,1724,1727-1731,1741,1745-1747,1751-1755,1799-1801,1859-1866,1868-1869,1894-1896,1905-1908, 1954, 1964-1966, 1969, 2066-2070, 2075-2079, 2108, 2138, 2143-2147, 2157-2160, 2193-2194, 2299-2300, 2312-2313, 2385, 2388, 2390 7. The oligonucleotide of any one of items 1-6, comprising the nucleobase sequence of any one of -2395, 2416-2418, 2460, 2462 or 2463.
(Item 15)
SEQ. 305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500-501, 503- 506, 508-512, 543-550, 552-560, 562, 582-585, 589-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 724, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961, 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1241-1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1319, 1321-1322, 1328, 1373, 1379-1383, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581-1582, 1584- 1589, 1591, 1601-1607, 1610, 1625, 1627-1629, 1631-1638, 1650-1655, 1659, 1665, 1668-1675, 1713-1714, 1716-1722, 1727-1731, 1745, 1747, 1751- 1755; 2158-2160, 2193-2194, 2299, 2300, 2313, 2385, 2388, 2390-2392, 2394-2395, 2418, 2460 or 2462-2463, comprising the nucleobase sequence of any one of item 1 or 6. The oligonucleotide according to any one of 6 above.
(Item 16)
SEQ. 352-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 460, 479, 482-486, 488-492, 497-498, 500-501, 503-506, 508-512, 544-550, 553-558, 560, 582-585, 589, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 770-771, 812- 816, 838-842, 845-851, 856, 883, 885, 889, 893, 895-897, 936, 940, 945, 961, 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1244, 1246-1249, 1251-1252, 1254-1255, 1257-1259, 1268, 1319, 1321-1322, 1380-1381, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1540, 1565-1566, 1579, 1581-1582, 1584-1589, 1591, 1601-1604, 1606-1607, 1610, 1625, 1627-1629, 1631-1638, 1651-1654, 1668, 1670-1674, 1714, 1717-1722, 1727-1731, 1745, 1751-1755, 1799, 1861, 1869, 1908, 1964, 1966, 2066-2069, 2075-2076, 7. The oligonucleotide of any one of items 1-6, comprising the nucleobase sequence of any one of 2078-2079, 2108, 2144-2145, 2158-2160, 2193, 2385, 2390 or 2460.
(Item 17)
SEQ. any one nucleic acid of 705-707, 839-842, 848, 1042-1045, 1172, 1255, 1454-1457, 1477-1499, 1538, 1539, 1581, 1582, 1606, 1607, 1610 or 1631-1633 7. The oligonucleotide according to any one of items 1 to 6, comprising a base sequence.
(Item 18)
SEQ. any one of items 1 to 6, comprising the nucleobase sequence of any one of 1581, 1582, 1587, 1601, 1602, 1606, 1607, 1610, 1631-1633, 1719, 1721, 1730, 1731, 1861 or 2068 The oligonucleotide according to item 1.
(Item 19)
SEQ. 7. The oligonucleotide of any one of items 1-6, comprising the nucleobase sequence of any one of 1668-1675 or 1862-1869.
(Item 20)
7. The oligonucleotide of any one of items 1-6, wherein said nucleobase sequence of said oligonucleotide consists of any one of SEQ ID NOs: 6-2545.
(Item 21)
SEQ. 295-296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500-501, 503-512, 543-550, 552-560, 562, 582-585, 588-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 724-725, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961, 965-968, 972-973, 999, 1007, 1016-1017, 1019, 1021-1022, 1036, 1040-1045, 1047, 1170, 1172-1173, 1211, 1216, 1222, 1235, 1240-1242, 1244- 1249,1251-1252,1254-1259,1268,1316,1318-1322,1328-1329,1373-1375,1379-1383,1386-1387,1407-1408,1433-1435,1450-1451,1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581-1589, 1591, 1600-1607, 1610, 1625, 1627-1629, 1631-1639, 1643, 1650-1660, 1663- 1665,1668-1675,1713-1714,1716-1722,1724,1727-1731,1741,1745-1747,1751-1755,1799-1801,1859-1866,1868-1869,1894-1896,1905-1908, 1954, 1964-1966, 1969, 2066-2070, 2075-2079, 2108, 2138, 2143-2147, 2157-2160, 2193-2194, 2299-2300, 2312-2313, 2385, 2388, 2390 7. The oligonucleotide of any one of items 1-6, consisting of the nucleobase sequence of any one of -2395, 2416-2418, 2460, 2462 or 2463.
(Item 22)
SEQ. 305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500-501, 503- 506, 508-512, 543-550, 552-560, 562, 582-585, 589-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 724, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961, 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1241-1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1319, 1321-1322, 1328, 1373, 1379-1383, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581-1582, 1584- 1589, 1591, 1601-1607, 1610, 1625, 1627-1629, 1631-1638, 1650-1655, 1659, 1665, 1668-1675, 1713-1714, 1716-1722, 1727-1731, 1745, 1747, 1751- 1755; 2158-2160, 2193-2194, 2299, 2300, 2313, 2385, 2388, 2390-2392, 2394-2395, 2418, 2460 or 2462-2463, item 1 7. The oligonucleotide according to any one of 6.
(Item 23)
SEQ. 352-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 460, 479, 482-486, 488-492, 497-498, 500-501, 503-506, 508-512, 544-550, 553-558, 560, 582-585, 589, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 770-771, 812- 816, 838-842, 845-851, 856, 883, 885, 889, 893, 895-897, 936, 940, 945, 961, 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1244, 1246-1249, 1251-1252, 1254-1255, 1257-1259, 1268, 1319, 1321-1322, 1380-1381, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1540, 1565-1566, 1579, 1581-1582, 1584-1589, 1591, 1601-1604, 1606-1607, 1610, 1625, 1627-1629, 1631-1638, 1651-1654, 1668, 1670-1674, 1714, 1717-1722, 1727-1731, 1745, 1751-1755, 1799, 1861, 1869, 1908, 1964, 1966, 2066-2069, 2075-2076, 7. The oligonucleotide according to any one of items 1 to 6, consisting of the nucleobase sequence of any one of 2078-2079, 2108, 2144-2145, 2158-2160, 2193, 2385, 2390 or 2460.
(Item 24)
SEQ. any one nucleic acid of 705-707, 839-842, 848, 1042-1045, 1172, 1255, 1454-1457, 1477-1499, 1538, 1539, 1581, 1582, 1606, 1607, 1610 or 1631-1633 7. The oligonucleotide according to any one of items 1 to 6, which consists of a base sequence.
(Item 25)
SEQ. any one of items 1 to 6, consisting of the nucleobase sequence of any one of 1581, 1582, 1587, 1601, 1602, 1606, 1607, 1610, 1631-1633, 1719, 1721, 1730, 1731, 1861 or 2068 The oligonucleotide according to item 1.
(Item 26)
SEQ. 7. The oligonucleotide according to any one of items 1 to 6, consisting of the nucleobase sequence of any one of 1668-1675 or 1862-1869.
(Item 27)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 50% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells, as determined using a cellular assay.
(Item 28)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 60% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells, as determined using a cellular assay.
(Item 29)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 70% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells, as determined using a cellular assay.
(Item 30)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 85% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells, as determined using a cellular assay.
(Item 31)
27. The oligonucleotide of any one of items 1-26, which at 2 nM exhibits at least 50% inhibition of mRNA when compared to control cells, as determined using a cellular assay.
(Item 32)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 60% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells, as determined using a cellular assay.
(Item 33)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 70% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells, as determined using a cellular assay.
(Item 34)
27. The oligonucleotide of any one of items 1-26, which exhibits at least 85% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells, as determined using a cellular assay.
(Item 35)
35. The oligonucleotide of any one of items 1-34, comprising at least one alternative internucleoside linkage.
(Item 36)
36. The oligonucleotide of item 35, wherein said at least one alternative internucleoside linkage is a phosphorothioate internucleoside linkage.
(Item 37)
36. The oligonucleotide of item 35, wherein said at least one alternative internucleoside linkage is a 2'-alkoxy internucleoside linkage.
(Item 38)
36. The oligonucleotide of item 35, wherein said at least one alternative internucleoside linkage is an alkyl phosphate internucleoside linkage.
(Item 39)
39. Oligonucleotide according to any one of items 1 to 38, comprising at least one alternative nucleobase.
(Item 40)
40. The oligonucleotide of item 39, wherein said alternative nucleobase is 5'-methylcytosine, pseudouridine or 5-methoxyuridine.
(Item 41)
41. Modified oligonucleotide according to any one of items 1 to 40, comprising at least one alternative sugar moiety.
(Item 42)
42. The modified oligonucleotide of item 41, wherein said alternative sugar moiety is 2'-OMe or a bicyclic nucleic acid.
(Item 43)
43. The oligonucleotide of any one of items 1-42, further comprising a ligand conjugated to the 5' or 3' end of said oligonucleotide via a monovalent or branched bivalent or trivalent linker.
(Item 44)
44. The oligonucleotide of any one of items 1-43, comprising a region complementary to at least 17 contiguous nucleotides of the MSH3 gene.
(Item 45)
44. The oligonucleotide of any one of items 1-43, comprising a region complementary to at least 19 contiguous nucleotides of the MSH3 gene.
(Item 46)
44. The oligonucleotide of any one of items 1-43, comprising a region complementary to 19-23 contiguous nucleotides of the MSH3 gene.
(Item 47)
44. The oligonucleotide of any one of items 1-43, comprising a region complementary to 19 contiguous nucleotides of the MSH3 gene.
(Item 48)
44. The oligonucleotide of any one of items 1-43, comprising a region complementary to 20 contiguous nucleotides of the MSH3 gene.
(Item 49)
44. The oligonucleotide of any one of items 1-43, which is about 15-25 nucleosides long.
(Item 50)
44. The oligonucleotide of any one of items 1-43, which is 20 nucleosides long.
(Item 51)
51. A pharmaceutical composition comprising one or more of the oligonucleotides of any one of items 1-50 and a pharmaceutically acceptable carrier or excipient.
(Item 52)
51. A composition comprising one or more of the oligonucleotides of any one of items 1 to 50 and lipid nanoparticles, polyplex nanoparticles, lipoplex nanoparticles or liposomes.
(Item 53)
51. A method of inhibiting transcription of MSH3 in a cell, comprising exposing the cell to one of the oligonucleotides of any one of items 1 to 50, for a period of time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene. contacting with one or more of the pharmaceutical compositions of item 51 or the composition of item 52 to inhibit expression of said MSH3 gene in said cells.
(Item 54)
A method of treating, preventing or delaying progression of a trinucleotide repeat expansion disorder in a subject in need of treatment, prevention or delaying progression of a trinucleotide repeat expansion disorder, said subject comprising: A method comprising administering one or more of the oligonucleotides of any one of claims, the pharmaceutical composition of item 51 or the composition of item 52.
(Item 55)
51. A method of reducing the level and/or activity of MSH3 in a cell of a subject identified as having a trinucleotide repeat expansion disorder, said cell comprising: A method comprising contacting with one or more of the pharmaceutical compositions according to item 51 or the compositions according to item 52.
(Item 56)
A method for inhibiting expression of the MSH3 gene in a cell, said cell being treated with one or more of the oligonucleotides of any one of items 1 to 50, the pharmaceutical composition of item 51 or contacting with the composition of item 52 and maintaining said cell for a period of time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene, thereby inhibiting expression of said MSH3 gene in said cell A method, including steps.
(Item 57)
A method of reducing trinucleotide repeat expansion in a cell, said cell comprising one or more of the oligonucleotides of any one of items 1 to 50, the pharmaceutical composition of item 51 or the pharmaceutical composition of item 52. A method comprising contacting with the composition described in .
(Item 58)
58. The method of items 56 or 57, wherein said cell is in a subject.
(Item 59)
59. The method of any one of items 54, 55 and 58, wherein said subject is a human.
(Item 60)
59. The method of any one of items 54-58, wherein the cells are central nervous system cells or muscle cells.
(Item 61)
The method of any one of items 54, 55 and 58-60, wherein said subject is identified as having a trinucleotide repeat expansion disorder.
(Item 62)
62. The method of any one of items 54, 55 and 57-61, wherein said trinucleotide repeat expansion disorder is polyglutamine disease.
(Item 63)
The polyglutamine disease includes dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, 63. The method of item 62, wherein the method is selected from the group consisting of Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17 and Huntington's disease-like 2.
(Item 64)
62. The method of any one of items 54-61, wherein said trinucleotide repeat expansion disorder is a non-polyglutamine disease.
(Item 65)
The non-polyglutamine disease is fragile X syndrome, fragile X-related tremor/ataxia syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia 12 oculopharyngeal muscular dystrophy, fragile X-associated premature ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy.
(Item 66)
One or more oligonucleotides according to any one of items 1 to 50, a pharmaceutical composition according to item 51 or a composition according to item 52 for use in the prevention or treatment of a trinucleotide repeat expansion disorder thing.
(Item 67)
The trinucleotide repeat expansion disorder is dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-related early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 69. An oligonucleotide, pharmaceutical composition or composition for use according to item 68, selected from
(Item 68)
68. Oligonucleotide, pharmaceutical composition or composition for use according to item 66 or 67, wherein said trinucleotide repeat expansion disorder is Huntington's disease.
(Item 69)
68. The oligonucleotide, pharmaceutical composition or composition of item 66 or 67, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.
(Item 70)
Oligonucleotide, pharmaceutical composition or composition for use according to item 66 or 67, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.
(Item 71)
71. The oligonucleotide, pharmaceutical composition or composition of any one of items 66-70, wherein said modified oligonucleotide, pharmaceutical composition or composition is administered intrathecally.
(Item 72)
71. The oligonucleotide, pharmaceutical composition or composition of any one of items 66-70, wherein said modified oligonucleotide, pharmaceutical composition or composition is administered intracerebroventricularly.
(Item 73)
71. The oligonucleotide, pharmaceutical composition or composition of any one of items 66-70, administered intramuscularly.
(Item 74)
A method of treating, preventing or delaying progression of a disorder in a subject in need of treating, preventing or delaying progression of a disorder, said subject suffering from a trinucleotide repeat expansion disorder, said subject comprising: , administering one or more of the oligonucleotides of any one of items 1 to 50, the pharmaceutical composition of item 51 or the composition of item 52.
(Item 75)
75. The method of item 74, further comprising administering an additional therapeutic agent.
(Item 76)
76. The method of item 75, wherein said additional therapeutic agent is another oligonucleotide that hybridizes to the mRNA encoding the huntingtin gene.
(Item 77)
A method of preventing or delaying the progression of a trinucleotide repeat expansion disorder in a subject, wherein the subject comprises: A method comprising administering one or more of the oligonucleotides of any one of claims, the pharmaceutical composition of item 51 or the composition of item 52.
(Item 78)
The trinucleotide repeat expansion disorder is dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-related early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 78. The method of item 77, selected from
(Item 79)
79. The method of items 77 or 78, wherein said trinucleotide repeat expansion disorder is Huntington's disease.
(Item 80)
79. The method of items 77 or 78, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.
(Item 81)
79. The method of items 77 or 78, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.
(Item 82)
79. The method of item 77 or 78, further comprising administering an additional therapeutic agent.
(Item 83)
83. The method of item 82, wherein said additional therapeutic agent is an oligonucleotide that hybridizes to the mRNA encoding the huntingtin gene.
(Item 84)
progression of said trinucleotide repeat expansion disorder is at least 120 days, e.g., at least 6 months, at least 12 months, at least 2 years, at least 3 years, at least 4 years, at least 5 years, when compared to predicted progression; 84. The method of any one of items 77-83, delayed for at least 10 years or longer.
(Item 85)
One or more oligonucleotides according to any one of items 1 to 50, a pharmaceutical composition according to item 51, for use in preventing or delaying the progression of a trinucleotide repeat expansion disorder in a subject or the composition of item 52.
(Item 86)
The trinucleotide repeat expansion disorder is dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-related early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 86. The oligonucleotide, pharmaceutical composition or composition of item 85, selected from
(Item 87)
87. The oligonucleotide, pharmaceutical composition or composition of item 85 or 86, wherein said trinucleotide repeat expansion disorder is Huntington's disease.
(Item 88)
87. The oligonucleotide, pharmaceutical composition or composition of item 85 or 86, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.
(Item 89)
87. The oligonucleotide, pharmaceutical composition or composition of items 85 or 86, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.
(Item 90)
progression of said trinucleotide repeat expansion disorder is at least 120 days, e.g., at least 6 months, at least 12 months, at least 2 years, at least 3 years, at least 4 years, at least 5 years, when compared to predicted progression; 90. The oligonucleotide, pharmaceutical composition or composition according to any one of items 85-89, which is delayed for at least 10 years or longer.

Claims

A single-stranded oligonucleotide 10-30 linked nucleosides in length, said oligonucleotide comprising a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene.

The oligonucleotide is
(a) a DNA core sequence comprising linked deoxyribonucleosides;
(b) a 5' flanking sequence comprising linked nucleosides; and (c) a 3' flanking sequence comprising linked nucleosides,
said DNA core comprises a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene and is positioned between said 5′ flanking sequence and said 3′ flanking sequence; said 2. The oligonucleotide of claim 1, wherein the 5' flanking sequence and said 3' flanking sequence each comprise at least two linked nucleosides; at least one nucleoside of each flanking sequence comprises an alternate nucleoside.

A composition for inhibiting expression of the human MSH3 gene in a cell, said composition comprising: a single-stranded oligonucleotide of 10-30 linked nucleosides in length, said oligonucleotide directed against the MSH3 gene comprising a region of at least 10 contiguous nucleobases having at least 80% complementarity with each other.

The oligonucleotide is
(a) a DNA core comprising linked deoxyribonucleosides;
(b) a 5' flanking sequence comprising linked nucleosides; and (c) a 3' flanking sequence comprising linked nucleosides,
said DNA core comprises a region of at least 10 contiguous nucleobases having at least 80% complementarity to the MSH3 gene and is positioned between said 5′ flanking sequence and said 3′ flanking sequence; said 4. The composition of claim 3, wherein the 5' flanking sequence and said 3' flanking sequence each comprise at least two linked nucleosides; at least one nucleoside of each flanking sequence comprises an alternate nucleoside.

5. The oligonucleotide of claim 1 or 2 or the composition of claim 3 or 4, wherein said region of at least 10 nucleobases has at least 90% complementarity to the MSH3 gene.

6. The oligonucleotide of any one of claims 1 , 2 and 5 or any one of claims 3-5, wherein said region of at least 10 nucleobases has at least 95% complementarity to the MSH3 gene. 10. The composition of claim 1 .

155-199, 355-385, 398-496, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~903, 912~974, 984~1047, 1054~1098, 1114~1179, 1200~1227, 1294~1337, 1392~1417, 1467~1493, 1517~1630, 1665~1747, 1768~1866 ,2029-2063,2087-2199,2262-2293,2304-2330,2371-2410,2432-2458,2494-2521,2539-2647,2679-2713,2727-2753,2767-2920,2933-3000,3046 complementary at one or more of positions -3073, 31323245, 3266-3306, 3397-3484, 3528-3575, 3591-3617, 3753-3792, 3901-3936, 4074-4101 or 4281-4319 , an oligonucleotide according to any one of claims 1 , 2, 5 and 6 or a composition according to any one of claims 3-6 .

155-199, 359-385, 398-496, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~974, 984~1098, 1114~1179, 1200~1227, 1294~1337, 1392~1417, 1467~1493, 1517~1630, 1665~1747, 1834~1866, 2029~2056, 2093~2199 ,2262-2293,2304-2329,2371-2410,2433-2458,2494-2521,2539-2647,2679-2713,2727-2753,2767-2920,2933-3000,3046-3072,3132-3245,3266 complementary at one or more of positions 3303, 3397-3484, 3528-3575, 3591-3617, 3753-3792, 3901-3936, 4076-4101 or 4281-4319 . , 5 and 6 or a composition according to any one of claims 3-6 .

155-196, 359-385, 413-462, 559-589, 676-724, 762 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~810, 876~974, 984~1096, 1114~1179, 1200~1227, 1294~1337, 1467~1493, 1517~1630, 1665~1747, 1834~1866, 2029~2056, 2093~2199, 2265~2293 ,2378-2410,2433-2458,2494-2521,2539-2647,2679-2712,2727-2753,2767-2919,2934-3000,3046-3071,3144-3183,3220-3245,3397-3484,3534 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6, or the Item 7. The composition according to any one of Items 3 to 6 .

435-462, 559-584, 763-808, 876-902, 931-958, 1001 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 ~1083, 1114-1179, 1294-1337, 1544-1578, 1835-1863, 2031-2056, 2144-2169, 2543-2577, 2590-2615, 2621-2647, 2685-2711, 2769-2795 or 2816-2868 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the composition of any one of claims 3-6, which is complementary at one or more of the positions. .

876-902, 930-958, 1056-1081, 1114-1139, 1154-1179, 1310 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 1 of -1337, 1546-1571, 1836-1862, 2141-2199, 2267-2292, 2540-2580, 2620-2647, 2686-2711, 2769-2868, 2939-2976, 3144-3169 or 3399-3424 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the composition of any one of claims 3-6, which is complementary at one or more positions.

984-1021, 1467-1493, 1722-1747, 1767-1802, 1833-1861, 2385 of said MSH3 gene for said region of at least 10 nucleobases corresponding to the sequence of reference mRNA NM_002439.4 2410, 2554-2581, 2816-2845 , 2861-2920 or 3151-3183. 7. An oligonucleotide or composition according to any one of claims 3-6 .

The oligonucleotide of any one of claims 1 , 2, 5 and 6 or any of claims 3-6, wherein said oligonucleotide comprises the nucleobase sequence of any one of SEQ ID NOs: 6-2545 A composition according to claim 1 .

SEQ ID NOs: 20, 22-29, 31-32, 77-78, 81-82, 115, 117, 130, 132-134, 144-145, 147, 167-168, 210, 212-215 , 290-293, 295-296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493 , 497-498, 500-501, 503-512, 543-550, 552-560, 562, 582-585, 588-591, 603-604, 611, 613-616, 659, 661, 699-700, 702 , 705-707, 724-725, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955 , 959-961, 965-968, 972-973, 999, 1007, 1016-1017, 1019, 1021-1022, 1036, 1040-1045, 1047, 1170, 1172-1173, 1211, 1216, 1222, 1235, 1240 ~1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1322, 1328-1329, 1373-1375, 1379-1383, 1386-1387, 1407-1408, 1433-1435, 1450-1451 and ~1660, 1663-1665, 1668-1675, 1713-1714, 1716-1722, 1724, 1727-1731, 1741, 1745-1747, 1751-1755, 1799-1801, 1859-1866, 1868-1869, 1894-1896 , 1905-1908, 1954, 1964-1966, 1969, 2066-2070, 2075-2079, 2108, 2138, 2143-2147, 2157-2160, 2193-2194, 2299-2300, 2312-2313, 2 385, 2388, 2390-2395, 2416-2418, 2460, 2462 or 2463. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or claim Item 7. The composition according to any one of Items 3 to 6 .

SEQ ID NOs: 20, 22, 25-29, 31-32, 81-82, 115, 130, 132-134, 144, 145, 147, 168, 210, 212-215, 290-293, 295 ~296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500 ~501, 503-506, 508-512, 543-550, 552-560, 562, 582-585, 589-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705 ~707, 724, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961 , 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1241-1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1319, 1321 ~1322, 1328, 1373, 1379-1383, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581 ~1582, 1584-1589, 1591, 1601-1607, 1610, 1625, 1627-1629, 1631-1638, 1650-1655, 1659, 1665, 1668-1675, 1713-1714, 1716-1722, 1727-1731, 1745 , 1747,1751-1755,1799-1800,1859,1861-1862,1865-1866,1868-1869,1895-1896,1905-1908,1954,1694-1966,2066-2070,2075-2079,2108,2138 any one nucleus of 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the composition of any one of claims 3-6, comprising an acid-base sequence .

SEQ ID NOs: 20, 25-29, 32, 81-82, 130, 133-134, 144-145, 147, 210, 212-213, 215, 290-293, 295-296, 299-304 , 309, 351, 352-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 460, 479, 482-486, 488-492, 497-498, 500-501 , 503-506, 508-512, 544-550, 553-558, 560, 582-585, 589, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705-707, 770 ~771, 812~816, 838~842, 845~851, 856, 883, 885, 889, 893, 895~897, 936, 940, 945, 961, 965~968, 972~973, 1041~1045, 1047 and and ,1627-1629,1631-1638,1651-1654,1668,1670-1674,1714,1717-1722,1727-1731,1745,1751-1755,1799,1861,1869,1908,1964,1966,2066-2069 , 2075-2076, 2078-2079, 2108, 2144-2145, 2158-2160, 2193 , 2385, 2390 or 2460. 7. An oligonucleotide according to one or a composition according to any one of claims 3-6 .

SEQ ID NOs: 145, 147, 210, 352, 365, 366, 407, 408, 439-442, 444, 492, 500, 504, 511, 512, 544-547, 582, 604, 616, 699 , 700, 702, 705-707, 839-842, 848, 1042-1045, 1172, 1255, 1454-1457, 1477-1499, 1538, 1539, 1581, 1582, 1606, 1607, 1610 or 1631-1633 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the composition of any one of claims 3-6, comprising any one of the nucleobase sequences .

SEQ ID NOS: 407, 408, 441, 442, 444, 545, 582, 616, 705-707, 841, 1043, 1044, 1252, 1255, 1268, 1321, 1451, 1454-1460, 1497-1499 , 1538, 1539, 1581, 1582, 1587, 1601, 1602, 1606, 1607, 1610, 1631-1633, 1719, 1721, 1730, 1731, 1861 or 2068. An oligonucleotide according to any one of claims 1 , 2, 5 and 6 or a composition according to any one of claims 3-6 .

SEQ ID NOS: 479, 482-491, 770, 771, 973, 998-1000, 1007, 1008, 1040-1043, 1387, 1454, 1456, 1459-1461, 1538, 1539, 1606, 1607, 1610 , 1643-1665 , 1668-1675 or 1862-1869. A composition according to any one of clauses .

The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the oligonucleotide of claims 3-6 , wherein said nucleobase sequence of said oligonucleotide consists of any one of SEQ ID NOs: 6-2545 A composition according to any one of the preceding claims .

SEQ ID NOs: 20, 22-29, 31-32, 77-78, 81-82, 115, 117, 130, 132-134, 144-145, 147, 167-168, 210, 212-215 , 290-293, 295-296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493 , 497-498, 500-501, 503-512, 543-550, 552-560, 562, 582-585, 588-591, 603-604, 611, 613-616, 659, 661, 699-700, 702 , 705-707, 724-725, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955 , 959-961, 965-968, 972-973, 999, 1007, 1016-1017, 1019, 1021-1022, 1036, 1040-1045, 1047, 1170, 1172-1173, 1211, 1216, 1222, 1235, 1240 ~1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1322, 1328-1329, 1373-1375, 1379-1383, 1386-1387, 1407-1408, 1433-1435, 1450-1451 and ~1660, 1663-1665, 1668-1675, 1713-1714, 1716-1722, 1724, 1727-1731, 1741, 1745-1747, 1751-1755, 1799-1801, 1859-1866, 1868-1869, 1894-1896 , 1905-1908, 1954, 1964-1966, 1969, 2066-2070, 2075-2079, 2108, 2138, 2143-2147, 2157-2160, 2193-2194, 2299-2300, 2312-2313, 2 385, 2388, 2390-2395, 2416-2418, 2460, 2462 or 2463, consisting of the nucleobase sequence of any one of claims 1 , 2, 5 and 6, or claim Item 7. The composition according to any one of Items 3 to 6 .

SEQ ID NOs: 20, 22, 25-29, 31-32, 81-82, 115, 130, 132-134, 144, 145, 147, 168, 210, 212-215, 290-293, 295 ~296, 299-305, 309, 351-359, 361-362, 365-366, 368, 407-409, 432, 437-442, 444, 459-460, 479, 482-493, 497-498, 500 ~501, 503-506, 508-512, 543-550, 552-560, 562, 582-585, 589-591, 603-604, 611, 613-616, 659, 661, 699-700, 702, 705 ~707, 724, 770-771, 812-816, 838-842, 845-852, 856, 883-885, 889, 893-897, 936, 940-941, 945, 948, 950, 955, 959-961 , 965-968, 972-973, 1041-1045, 1047, 1170, 1172, 1216, 1222, 1235, 1241-1242, 1244-1249, 1251-1252, 1254-1259, 1268, 1316, 1318-1319, 1321 ~1322, 1328, 1373, 1379-1383, 1386-1387, 1408, 1433-1435, 1450-1451, 1454-1461, 1476-1477, 1496-1499, 1532, 1538-1541, 1565-1566, 1579, 1581 ~1582, 1584-1589, 1591, 1601-1607, 1610, 1625, 1627-1629, 1631-1638, 1650-1655, 1659, 1665, 1668-1675, 1713-1714, 1716-1722, 1727-1731, 1745 , 1747,1751-1755,1799-1800,1859,1861-1862,1865-1866,1868-1869,1895-1896,1905-1908,1954,1694-1966,2066-2070,2075-2079,2108,2138 any one nucleus of 7. An oligonucleotide according to any one of claims 1 , 2, 5 and 6 or a composition according to any one of claims 3 to 6, which consists of an acid-base sequence.

SEQ ID NOs: 145, 147, 210, 352, 365, 366, 407, 408, 439-442, 444, 492, 500, 504, 511, 512, 544-547, 582, 604, 616, 699 , 700, 702, 705-707, 839-842, 848, 1042-1045, 1172, 1255, 1454-1457, 1477-1499, 1538, 1539, 1581, 1582, 1606, 1607, 1610 or 1631-1633 7. The oligonucleotide of any one of claims 1 , 2, 5 and 6 or the composition of any one of claims 3-6, consisting of any one of the nucleobase sequences .

SEQ ID NOS: 479, 482-491, 770, 771, 973, 998-1000, 1007, 1008, 1040-1043, 1387, 1454, 1456, 1459-1461, 1538, 1539, 1606, 1607, 1610 , 1643-1665, 1668-1675 or 1862-1869, the oligonucleotide of any one of claims 1 , 2, 5 and 6 or the A composition according to any one of the preceding claims .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 50% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 60% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 70% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 85% mRNA inhibition at an oligonucleotide concentration of 20 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any one of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 50% mRNA inhibition at 2 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of claim 3 or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 60% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 70% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

27. Any of claims 1 , 2 and 5-26, wherein said oligonucleotide exhibits at least 85% mRNA inhibition at an oligonucleotide concentration of 2 nM when compared to control cells as determined using a cellular assay. 27. The oligonucleotide of any one of claims or the composition of any one of claims 3-26 .

35. The oligonucleotide of any one of claims 1 , 2 and 5-34 or the composition of any one of claims 3-34, wherein said oligonucleotide comprises at least one alternative internucleoside linkage. things .

36. The oligonucleotide or composition of claim 35, wherein said at least one alternative internucleoside linkage is a phosphorothioate internucleoside linkage.

36. The oligonucleotide or composition of claim 35, wherein said at least one alternative internucleoside linkage is a 2'-alkoxy internucleoside linkage.

36. The oligonucleotide or composition of claim 35, wherein said at least one alternative internucleoside linkage is an alkyl phosphate internucleoside linkage.

39. The oligonucleotide of any one of claims 1 , 2 and 5-38 or the composition of any one of claims 3-38, wherein said oligonucleotide comprises at least one alternative nucleobase. .

40. The oligonucleotide or composition of claim 39, wherein said alternative nucleobase is 5'-methylcytosine, pseudouridine or 5-methoxyuridine.

The modified oligonucleotide of any one of claims 1 , 2 and 5-40 or the modified oligonucleotide of any one of claims 3-40, wherein said oligonucleotide comprises at least one alternative sugar moiety. composition .

42. The modified oligonucleotide or composition of claim 41, wherein said alternative sugar moieties are 2'-OMe or bicyclic nucleic acids.

of claims 1 , 2 and 5-42, wherein said oligonucleotide further comprises a ligand conjugated to the 5' or 3' end of said oligonucleotide via a monovalent or branched bivalent or trivalent linker. 43. The oligonucleotide of any one of claims or the composition of any one of claims 3-42 .

43. The oligonucleotide of any one of claims 1 , 2 and 5-43 or claims 3-43, wherein said oligonucleotide comprises a region complementary to at least 17 contiguous nucleotides of the MSH3 gene. A composition according to any one of the preceding claims .

43. The oligonucleotide of any one of claims 1 , 2 and 5-43 or claims 3-43, wherein said oligonucleotide comprises a region complementary to at least 19 contiguous nucleotides of the MSH3 gene. A composition according to any one of the preceding claims .

The oligonucleotide of any one of claims 1 , 2 and 5 to 43 or from claims 3, wherein said oligonucleotide comprises a region complementary to 19-23 contiguous nucleotides of the MSH3 gene. 44. The composition of any one of Clauses 43 .

44. The oligonucleotide of any one of claims 1 , 2 and 5-43 or the oligonucleotide of claims 3-43, wherein said oligonucleotide comprises a region complementary to 19 contiguous nucleotides of the MSH3 gene A composition according to any one of the preceding claims .

44. The oligonucleotide of any one of claims 1 , 2 and 5-43 or the oligonucleotide of claims 3-43, wherein said oligonucleotide comprises a region complementary to 20 contiguous nucleotides of the MSH3 gene A composition according to any one of clauses .

The oligonucleotide of any one of claims 1 , 2 and 5-43 or the composition of any one of claims 3-43, wherein said oligonucleotide is about 15-25 nucleosides in length.

44. The oligonucleotide of any one of claims 1 , 2 and 5-43 or the composition of any one of claims 3-43, wherein said oligonucleotide is 20 nucleosides long.

one or more of the oligonucleotides of any one of claims 1 , 2 and 5 to 50 or the composition of any one of claims 3 to 50 and a pharmaceutically acceptable carrier or Pharmaceutical compositions containing excipients.

one or more of the oligonucleotides according to any one of claims 1 , 2 and 5 to 50 or the composition according to any one of claims 3 to 50 and lipid nanoparticles, polyplex nanoparticles Compositions comprising particles, lipoplex nanoparticles or liposomes.

A composition comprising one or more of the oligonucleotides of any one of claims 1, 2 and 5-50, claims 3-50, for use in a method of inhibiting transcription of MSH3 in a cell 53. The composition of any one of claims 51, the pharmaceutical composition of claim 51 or the composition of claim 52, wherein the method comprises treating the cell for degradation of mRNA transcripts of the MSH3 gene. one or more of the oligonucleotides of any one of claims 1 , 2 and 5 to 50 , the composition of any one of claims 3 to 50 , for a period of time sufficient to obtain 53. A composition comprising contacting with the pharmaceutical composition of claim 51 or the composition of claim 52 to inhibit expression of said MSH3 gene in said cell.

51. Any of claims 1 , 2 and 5-50 for treating, preventing or delaying the progression of a trinucleotide repeat expansion disorder in a subject in need thereof. A composition comprising one or more of the oligonucleotides of claim 3, a composition of any one of claims 3 to 50, a pharmaceutical composition of claim 51 or a pharmaceutical composition of claim 52. composition .

51. The oligo of any one of claims 1, 2 and 5-50 for use in a method of reducing the level and/or activity of MSH3 in cells of a subject identified as having a trinucleotide repeat expansion disorder. A composition comprising one or more of the nucleotides, a composition according to any one of claims 3 to 50, a pharmaceutical composition according to claim 51 or a composition according to claim 52, wherein Said method comprises: said cell comprising one or more of the oligonucleotides of any one of claims 1 , 2 and 5-50 ; the composition of any one of claims 3-50 ; 53. A composition comprising contacting with the pharmaceutical composition of claim 51 or the composition of claim 52.

A composition comprising one or more of the oligonucleotides of any one of claims 1, 2 and 5 to 50 for use in a method for inhibiting expression of the MSH3 gene in a cell, claim 52. The composition of any one of claims 3 to 50, the pharmaceutical composition of claim 51 or the composition of claim 52, wherein the method comprises removing said cells from any of claims 1, 2 and one or more of the oligonucleotides according to any one of claims 5 to 50 , the composition according to any one of claims 3 to 50, the pharmaceutical composition according to claim 51 or the composition according to claim 52 and maintaining said cell for a time sufficient to obtain degradation of the mRNA transcript of the MSH3 gene, thereby inhibiting expression of said MSH3 gene in said cell. , composition .

A composition comprising one or more of the oligonucleotides of any one of claims 1, 2 and 5-50, claims 3-3, for use in a method of reducing trinucleotide repeat expansion in a cell 53. The composition according to any one of claims 50, the pharmaceutical composition according to claim 51 or the composition according to claim 52, wherein said method comprises converting said cells from claims 1, 2 and 5 to one or more of the oligonucleotides according to any one of claims 50 , the composition according to any one of claims 3 to 50 , the pharmaceutical composition according to claim 51 or the A composition, comprising contacting with the composition .

58. The composition of claim 56 or 57, wherein said cell is in a subject.

59. The composition of any one of claims 54, 55 and 58, wherein said subject is a human.

59. The composition of any one of claims 54-58, wherein the cells are central nervous system cells or muscle cells.

61. The composition of any one of claims 54, 55 and 58-60, wherein said subject has been identified as having a trinucleotide repeat expansion disorder.

62. The composition of any one of claims 54, 55 and 57-61, wherein said trinucleotide repeat expansion disorder is polyglutamine disease.

The polyglutamine disease includes dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, 63. The composition of claim 62 selected from the group consisting of Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17 and Huntington's disease-like 2.

62. The composition of any one of claims 54-61, wherein said trinucleotide repeat expansion disorder is a non-polyglutamine disease.

The non-polyglutamine disease is fragile X syndrome, fragile X-related tremor/ataxia syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia 12 65. The composition of claim 64, selected from the group consisting of Oculopharyngeal Muscular Dystrophy, Fragile X-associated premature ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy.

A composition comprising one or more oligonucleotides according to any one of claims 1 , 2 and 5-50, of claims 3-50, for use in the prevention or treatment of trinucleotide repeat expansion disorders. A composition according to any one of claims 51, a pharmaceutical composition according to claim 51 or a composition according to claim 52.

The trinucleotide repeat expansion disorder is dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-associated early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 69. The composition of claim 68, selected from

68. The composition of claim 66 or 67, wherein said trinucleotide repeat expansion disorder is Huntington's disease.

68. The composition of claim 66 or 67, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.

68. The composition of claim 66 or 67, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.

71. A composition according to any one of claims 66 to 70, characterized in that said composition is administered intrathecally.

71. A composition according to any one of claims 66 to 70, characterized in that said composition is administered intracerebroventricularly.

71. Composition according to any one of claims 66 to 70, characterized in that said composition is administered intramuscularly.

51. The oligonucleotide of any one of claims 1, 2 and 5-50 for treating, preventing or delaying the progression of a disorder in a subject in need thereof. a composition according to any one of claims 3 to 50, a pharmaceutical composition according to claim 51 or a composition according to claim 52, wherein said A composition , wherein the subject is suffering from a trinucleotide repeat expansion disorder.

75. The composition of claim 74, wherein said composition is administered in combination with an additional therapeutic agent.

76. The composition of claim 75, wherein said additional therapeutic agent is another oligonucleotide that hybridizes to the mRNA encoding the huntingtin gene.

A composition comprising one or more of the oligonucleotides of any one of claims 1 , 2 and 5-50 for preventing or delaying progression of trinucleotide repeat expansion disorder in a subject, claim A composition according to any one of claims 3 to 50 , a pharmaceutical composition according to claim 51 or a composition according to claim 52 .

The trinucleotide repeat expansion disorder is dentate nucleopallidal Louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-associated early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 78. The composition of claim 77, selected from

79. The composition of claim 77 or 78, wherein said trinucleotide repeat expansion disorder is Huntington's disease.

79. The composition of claim 77 or 78, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.

79. The composition of claim 77 or 78, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.

79. The composition of claims 77 or 78, characterized in that said composition is administered in combination with an additional therapeutic agent.

83. The composition of claim 82, wherein said additional therapeutic agent is an oligonucleotide that hybridizes to the mRNA encoding the huntingtin gene.

progression of said trinucleotide repeat expansion disorder is at least 120 days, e.g., at least 6 months, at least 12 months, at least 2 years, at least 3 years, at least 4 years, at least 5 years, when compared to predicted progression; 84. The composition of any one of claims 77-83, which is delayed for at least 10 years or longer.

51. A composition comprising one or more oligonucleotides according to any one of claims 1 , 2 and 5-50 for use in preventing or delaying progression of trinucleotide repeat expansion disorder in a subject. the composition of any one of claims 3 to 50 , the pharmaceutical composition of claim 51 or the composition of claim 52.

The trinucleotide repeat expansion disorder is dentate nucleopallidus louis body atrophy, Huntington's disease, spinobulbar muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia 3 Spinocerebellar ataxia type 6, Spinocerebellar ataxia type 7, Spinocerebellar ataxia type 17, Huntington's disease-like 2, Fragile X syndrome, Fragile X-related tremor/ataxia syndrome, Fragile XE mental retardation, Friedreich's ataxia myotonic dystrophy type 1, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, oculopharyngeal muscular dystrophy, fragile X-related early ovarian insufficiency, FRA2A syndrome, FRA7A syndrome and early infantile epileptic encephalopathy 86. The composition of claim 85, selected from

87. The composition of claim 85 or 86, wherein said trinucleotide repeat expansion disorder is Huntington's disease.

87. The composition of claim 85 or 86, wherein said trinucleotide repeat expansion disorder is Friedreich's ataxia.

87. The composition of claim 85 or 86, wherein said trinucleotide repeat expansion disorder is myotonic dystrophy type 1.

progression of said trinucleotide repeat expansion disorder is at least 120 days, e.g., at least 6 months, at least 12 months, at least 2 years, at least 3 years, at least 4 years, at least 5 years, when compared to predicted progression; 90. The composition of any one of claims 85-89, which is delayed for at least 10 years or longer.