JP2021531009A - 筋ジストロフィーに対するエクソンスキッピングオリゴマー - Google Patents
筋ジストロフィーに対するエクソンスキッピングオリゴマー Download PDFInfo
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
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Abstract
Description
本出願は、2018年7月27日に出願された米国仮出願第62/711,215号、および2019年6月28日に出願された米国仮出願第62/868,003号の利益を主張するものである。上記に参照される出願の教示全体は、参照によりそれらの全体が組み込まれる。
本出願は、ASCII形式で電子的に提出されており、かつ参照によりその全体が本明細書に組み込まれる、配列表を含有する。当該ASCIIの複写は2019年7月3日に作成され、名称は8166_02_WO00_SL.txt、サイズは28,526バイトである。
本開示は、ヒトジストロフィン遺伝子におけるエクソン2スキッピングに好適な新規のアンチセンスオリゴマーおよびその医薬組成物に関する。本開示はまた、新規のアンチセンスオリゴマーを使用してエクソン2スキッピングを誘導するための方法、エクソン2スキッピングに適しているジストロフィン遺伝子の変異を有する対象においてジストロフィンを産生するための方法、およびエクソン2スキッピングに適しているジストロフィン遺伝子の変異を有する対象を治療するための方法も提供する。
−C(O)(CH2)5NH−CPP;
−C(O)(CH2)2NH−CPP;
−C(O)(CH2)2NHC(O)(CH2)5NH−CPP;
−C(O)CH2NH−CPP;および以下の式:
−C(O)(CH2)5NH−CPP;
−C(O)(CH2)2NH−CPP;
−C(O)(CH2)2NHC(O)(CH2)5NH−CPP;
−C(O)CH2NH−CPP;および以下の式:
いくつかの実施形態において、Raは、アセチルである。
各Nuは、一緒になって標的化配列を形成する核酸塩基であり、
T’は、以下から選択される部分であり、
1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応する。
−C(O)(CH2)5NH−CPP;
−C(O)(CH2)2NH−CPP;
−C(O)(CH2)2NHC(O)(CH2)5NH−CPP;
−C(O)CH2NH−CPP;および以下の式:
−C(O)(CH2)5NH−CPP;
−C(O)(CH2)2NH−CPP;
−C(O)(CH2)2NHC(O)(CH2)5NH−CPP;
−C(O)CH2NH−CPP;および以下の式:
いくつかの実施形態において、Raは、アセチルである。
本明細書で使用される場合、「アルキル」という用語は、別段の定めがない限り、飽和直鎖または分岐炭化水素を指す。ある特定の実施形態において、アルキル基は、第一級、第二級、または第三級炭化水素である。ある特定の実施形態において、アルキル基は、1〜10個の炭素原子、すなわち、C1〜C10アルキルを含む。ある特定の実施形態において、アルキル基は、1〜6個の炭素原子、すなわち、C1〜C6アルキルを含む。この用語は、ハロゲン化アルキル基を含む、置換アルキル基および非置換アルキル基の両方を含む。ある特定の実施形態において、アルキル基は、フッ素化アルキル基である。アルキル基が置換され得る部分の非限定的な例は、当業者に既知のように、例えば、参照により本明細書に組み込まれるGreene,et al.,Protective Groups in Organic Synthesis,John Wiley and Sons,Second Edition,1991で教示されるように、保護されていないか、または必要に応じて保護されているかのいずれかの、ハロゲン(フルオロ、クロロ、ブロモ、もしくはヨード)、ヒドロキシル,アミノ、アルキルアミノ、アリールアミノ、アルコキシ、アリールオキシ、ニトロ、シアノ、スルホン酸、硫酸塩、ホスホン酸、リン酸塩、またはホスホン酸塩からなる群から選択される。ある特定の実施形態において、アルキル基は、メチル、CF3、CCl3、CFCl2、CF2Cl、エチル、CH2CF3、CF2CF3、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、t−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、3−メチルペンチル、2,2−ジメチルブチル、および2,3−ジメチルブチルからなる群から選択される。「アシル」という用語は、C(O)R11基(ここで、R11は、本明細書で定義されるようにH、アルキル、またはアリールを意味する)を指す。アシル基の例としては、ホルミル、アセチル、ベンゾイル、フェニルアセチル、および類似の基が挙げられる。
H#A/D(x:y)
A.エクソン2スキッピングを誘導するように設計されたアンチセンスオリゴマー
ある特定の実施形態において、本開示のアンチセンスオリゴマーは、ジストロフィン遺伝子のエクソン2、イントロン1、またはイントロン2標的領域に相補的であり、かつエクソン2スキッピングを誘導する。特に、本開示は、アニーリング部位として指定されるジストロフィンプレmRNAのエクソン2、イントロン1、またはイントロン2標的領域に相補的なアンチセンスオリゴマーに関する。いくつかの実施形態において、アニーリング部位は、以下のうちのいずれか1つである。
本開示のアンチセンスオリゴマーは、様々なアンチセンスオリゴマー化学物質を用いることができる。オリゴマー化学物質の例としては、モルホリノオリゴマー、ホスホロチオエート修飾オリゴマー、2’−O−メチル修飾オリゴマー、ペプチド核酸(PNA)、ロックド核酸(LNA)、ホスホロチオエートオリゴマー、2’−O−MOE修飾オリゴマー、2’−フルオロ修飾オリゴマー、2’−O,4’C−エチレン架橋核酸(ENA)、トリシクロ−DNA、トリシクロ−DNAホスホロチオエートサブユニット、2’−O−[2−(N−メチルカルバモイル)エチル]修飾オリゴマー(上記のいずれかの組み合わせを含む)が挙げられるが、これらに限定されない。ホスホロチオエートおよび2’−O−Me修飾化学物質を組み合わせて、2’−O−Me−ホスホロチオエート骨格を生成することができる。例えば、PCT公開第WO/2013/112053号および同第WO/2009/008725号(参照によりそれらの全体が本明細書に組み込まれる)を参照されたい。本開示のオリゴマー化学物質の例示的な実施形態が以下にさらに記載される。
ペプチド核酸(PNA)は、骨格がデオキシリボース骨格と構造的に同形であり、ピリミジンまたはプリン塩基が結合するN−(2−アミノエチル)グリシン単位からなる、DNAの類似体である。天然ピリミジンおよびプリン塩基を含有するPNAは、ワトソン−クリック塩基対合則に従い相補的なオリゴマーにハイブリダイズし、塩基対認識の点でDNAを模倣する。PNAの骨格は、ホスホジエステル結合ではなくペプチド結合によって形成され、アンチセンス用途(以下の構造を参照)によく適したものになる。骨格は非荷電性であり、通常を超える熱安定性を示すPNA/DNAまたはPNA/RNA二本鎖をもたらす。PNAは、ヌクレアーゼまたはプロテアーゼによって認識されない。PNAの非限定的な例が以下に示される。
アンチセンスオリゴマーはまた、「ロックド核酸」サブユニット(LNA)を含有し得る。「LNA」は、架橋核酸(BNA)と呼ばれる修飾のクラスのメンバーである。BNAは、リボース環の立体構造をC30−エンド(ノーザン)糖パッカーにロックする共有結合を特徴とする。LNAの場合、架橋は、2’−O位置と4’−C位置との間のメチレンから構成される。LNAは、骨格の事前組織化および塩基スタッキングを増強して、ハイブリダイゼーションおよび熱安定性を高める。
アンチセンスオリゴマーはまた、アンロックド核酸(UNA)サブユニットを含有し得る。UNAおよびUNAオリゴマーは、サブユニットのC2’−C3’結合が切断されているRNAの類似体である。LNAは、(DNAおよびRNAと比較して)立体構造的に制限されるが、UNAは非常に可撓性である。UNAは、例えば、WO2016/070166に開示されている。UNAの非限定的な例が以下に示される。
「ホスホロチオエート」(またはS−オリゴ)は、正常なDNAのバリアントであり、非架橋酸素のうちの1つが硫黄によって置換されている。ホスホロチオエートの非限定的な例が以下に示される。
トリシクロ−DNA(tc−DNA)は、骨格の立体構造的柔軟性を制限し、ねじれ角γの骨格形状を最適化するために、各ヌクレオチドがシクロプロパン環の導入によって修飾される、拘束されたDNA類似体のクラスである。ホモ塩基アデニンおよびチミン含有tc−DNAは、相補的RNAと非常に安定したA−T塩基対を形成する。トリシクロDNAおよびその合成は、国際特許出願公開第WO2010/115993号に記載されており、これは参照によりその全体が本明細書に組み込まれる。本開示のアンチセンスオリゴマーは、1つ以上のトリシクロ−DNAサブユニットを組み込み得る。場合によっては、アンチセンスオリゴマーは、トリシクロ−DNAサブユニットから完全に構成され得る。
「2’−O−Meオリゴマー」分子は、リボース分子の2’−OH残基にメチル基を有する。2’−O−Me−RNAは、DNAと同じ(または類似の)挙動を示すが、ヌクレアーゼ分解から保護される。2’−O−Me−RNAはまた、さらなる安定化のためにホスホロチオエートオリゴマー(PTO)と組み合わせることができる。2’O−Meオリゴマー(ホスホジエステルまたはホスホロチオエート)は、当該技術分野の常用技術に従って合成することができる(例えば、Yoo et al.,Nucleic Acids Res.32:2008−16,2004(参照によりその全体が本明細書に組み込まれる)を参照)。2’O−Meオリゴマーの非限定的な例が以下に示される。
Rは、CH2CH2OCH3(メトキシエチルまたはMOE)であり、
X、Y、およびZは、それぞれ指定された5’−ウィング、中央ギャップ、および3’−ウィングの各領域内に含有されるヌクレオチドの数を表す。
MCEは、本開示のアンチセンスオリゴマーで有用な2’−O修飾リボヌクレオシドの別の例である。ここで、2’−OHは、ヌクレアーゼ耐性を高めるために2−(N−メチルカルバモイル)エチル部分へと誘導体化される。MCEオリゴマーの非限定的な例が以下に示される。
立体特異的オリゴマーは、各リン含有連結の立体化学が、実質的に立体的に純粋なオリゴマーが産生されるような合成方法によって固定されるものである。立体特異的オリゴマーの非限定的な例が以下に示される。
本開示の例示的な実施形態は、以下の一般構造の、
R200は、水素または細胞膜透過性ペプチドであり、R1は、C1−C6アルキルである。
各Nuは、一緒になって標的化配列を形成する核酸塩基であり、
式(I)中のT’は、以下から選択される部分であり、
1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
R200は、水素または細胞膜透過性ペプチドであり、1〜(n+1)個の各Nuは5’から3’に、以下のうちの1つにおける核酸塩基に対応し、
ある特定の実施形態において、本開示のアンチセンスオリゴマーは、RNA核酸塩基およびDNA核酸塩基(多くの場合、当該技術分野では単に「塩基」と称される)から構成される。RNA塩基は、アデニン(A)、ウラシル(U)、シトシン(C)、およびグアニン(G)として一般的に既知である。DNA塩基は、アデニン(A)、チミン(T)、シトシン(C)、およびグアニン(G)として一般的に既知である。様々な実施形態において、本開示のアンチセンスオリゴマーは、シトシン(C)、グアニン(G)、チミン(T)、アデニン(A)、5−メチルシトシン(5mC)、ウラシル(U)、およびヒポキサンチン(I)から構成される。
本明細書に記載されるアンチセンスオリゴマーのある特定の実施形態は、アミノまたはアルキルアミノなどの塩基性官能基を含有し得、ひいては薬学的に許容される酸と薬学的に許容される塩を形成することができる。この点における「薬学的に許容される塩」という用語は、本開示のアンチセンスオリゴマーの比較的非毒性の無機酸および有機酸付加塩を指す。これらの塩は、投与ビヒクルまたは剤形製造プロセスにおいて原位置で調製することができるか、または本開示の精製されたアンチセンスオリゴマーを、その遊離塩基形態で、好適な有機酸もしくは無機酸と別個に反応させ、その後の精製中にそのようにして形成された塩を単離することによって調製することができる。代表的な塩としては、臭化水素酸塩、塩酸塩、硫酸塩、重硫酸塩、リン酸塩、硝酸塩、酢酸塩、吉草酸塩、オレイン酸塩、パルミチン酸塩、ステアリン酸塩、ラウリン酸塩、安息香酸塩、乳酸塩、トシル酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、酒石酸塩、ナフチル酸塩、メシル酸塩、グルコヘプトン酸塩、ラクトビオン酸塩、およびラウリルスルホン酸塩などが挙げられる。(例えば、Berge et al.(1977)「Pharmaceutical Salts」,J.Pharm.Sci.66:1−19を参照)。
ある特定の実施形態において、本開示は、本明細書に記載されるアンチセンスオリゴマーまたはその薬学的に許容される塩の治療送達に好適な製剤または医薬組成物を提供する。したがって、ある特定の実施形態において、本開示は、1つ以上の薬学的に許容される担体(添加剤)および/または希釈剤と共に製剤化された、治療有効量の本明細書に記載される1つ以上のアンチセンスオリゴマーまたはその薬学的に許容される塩を含む、薬学的に許容される組成物を提供する。本開示のアンチセンスオリゴマーまたはその薬学的に許容される塩を単独で投与することは可能であるが、アンチセンスオリゴマーまたはその薬学的に許容される塩を医薬製剤(組成物)として投与することが好ましい。一実施形態において、製剤のアンチセンスオリゴマーまたはその薬学的に許容される塩は、式(III)または式(IV)に従う。
エクソンスキッピングを使用したジストロフィンリーディングフレームの回復
ジストロフィン遺伝子のアウトオブフレーム変異によって引き起こされるDMDの治療に対する潜在的な治療アプローチは、インフレーム変異によって引き起こされるBMDとして既知のより軽度な型のジストロフィン異常症によって示唆される。アウトオブフレーム変異をインフレーム変異に変換する能力は、仮定では、mRNAリーディングフレームを保持し、内部で短縮されたが機能的なジストロフィンタンパク質を産生する。本開示のアンチセンスオリゴマーまたはその薬学的に許容される塩は、これを達成するように設計された。
本開示はまた、遺伝的疾患を有する患者の治療のためのキットを提供し、そのキットは、好適な容器に包装された、少なくともアンチセンス分子(例えば、配列番号1〜39のいずれかに記載される塩基配列を含むアンチセンスオリゴマー)またはその薬学的に許容される塩を、その使用のための説明書と共に含む。キットは、緩衝液、安定剤などの周辺試薬も含有し得る。当業者であれば、上記方法の用途が、多くの他の疾患の治療における使用に好適なアンチセンス分子を特定するために幅広い用途を有することを理解するべきである。一実施形態において、キットは、式(I)〜(VI)のいずれかに従うアンチセンスオリゴマーまたはその薬学的に許容される塩を含む。
モルホリノサブユニットの調製
アンカー装填樹脂への活性化「テール」の導入を、固相合成中のサブユニットの組み込みに使用される手順によって、ジメチルイミダゾリジノン(DMI)中で実施する。
脱トリチル化溶液:4:1のジクロロメタン/トリフルオロエタノール溶液中の1%の4シアノピリジンおよびトリフルオロ酢酸(w/w);
中和溶液:5:1のジクロロメタン/イソプロパノール溶液中の3%のジイソプロピルエチルアミン;ならびに
カップリング溶液:1,3−ジメチルイミダゾリジノン(DMI)溶液中の所望の塩基および連結型の0.18M(または20サブユニットよりも長く成長しているオリゴマーについては0.24M)の活性化モルホリノサブユニットならびに0.4MのN−エチルモルホリン。
NCP2アンカー合成:
1.4−フルオロ−3−ニトロ安息香酸メチルの調製(1)
A.(Z)−メチル4−(3−ヒドロキシ−1−メトキシ−1−オキソブタ−2−エン−2−イル)−3−ニトロ安息香酸塩(2)
4.(4−(2−ヒドロキシプロピル)−3−ニトロフェニル)(4−トリチルピペラジン−1−イル)メタノンの調製
約52LのNMPおよび2300gのアミノメチルポリスチレン樹脂を、テフロン(登録商標)活栓を備えた75L固相合成反応器に充填し得る。樹脂を、NMP中で約2時間撹拌して膨潤させ、次いで排出する。樹脂を、1回の洗浄当たり4LのDCMで2回、次いで1回の洗浄当たり39Lの中和溶液で2回、次いで1回の洗浄当たり39LのDCMで2回洗浄する。NCP2アンカー溶液を撹拌樹脂溶液にゆっくりと添加し、室温で24時間撹拌し、次いで排出する。樹脂を、1回の洗浄当たり39LのNMPで4回、および1回の洗浄当たり39LのDCMで6回洗浄する。樹脂を、1/2の二炭酸ジエチル(DEDC)キャッピング溶液で30分間処理および撹拌し、排出し、残りの1/2のDEDCキャッピング溶液で30分間処理および撹拌し、排出する。樹脂を、1回の洗浄当たり39LのDCMで6回洗浄し、次いでオーブン内で3573.71gの一定重量のアンカー装填樹脂になるまで乾燥させる。
A.樹脂膨潤
750gのアンカー装填樹脂および10.5LのNMPのアリコートを、50Lのシラン処理した反応器に充填し、3時間撹拌し得る。NMPを排出し、アンカー装填樹脂を、それぞれ5.5LのDCMで2回、およびそれぞれ5.5Lの30% TFE/DCMで2回、洗浄する。
アンカー装填樹脂を、それぞれ5.5Lの30% TFE/DCMで3回洗浄し、排出し、5.5LのCYTFA溶液で15分間洗浄し、排出し、5.5LのCYTFA溶液で15分間、排出することなく再び洗浄し、それに122mLの1:1のNEM/DCMを充填し、懸濁液を2分間撹拌し、排出し得る。樹脂を、5.5Lの中和溶液で5分間、2回洗浄し、排出し、次いでそれぞれ5.5LのDCMで2回洗浄し、排出する。3LのDMI中の706.2gの活性化EG3テールおよび234mLのNEMの溶液を樹脂に充填し、室温で3時間撹拌し、排出し得る。樹脂を、1回の洗浄当たりそれぞれ5.5Lの中和溶液で5分間、2回、次いで5.5LのDCMで1回洗浄し、排出する。2680mLのNMP中の374.8gの無水安息香酸および195mLのNEMの溶液を充填し、15分間撹拌し、排出し得る。樹脂を、5.5Lの中和溶液で5分間撹拌し、次いで5.5LのDCMで1回、およびそれぞれ5.5Lの30% TFE/DCMで2回洗浄する。樹脂を、5.5Lの30% TFE/DCM中に懸濁し、14時間保持する。
各カップリングサイクルの前に、樹脂を、1)30% TFE/DCMで洗浄し、2)a)CYTFA溶液で15分間処理し、排出し、b)CYTFA溶液で15分間処理し、それに1:1のNEM/DCMを添加し、撹拌し、排出し、3)中和溶液で3回撹拌し、4)DCMで2回洗浄する。
各サブユニット溶液を排出した後、樹脂を、1)DCMで洗浄し、2)30% TFE/DCMで2回洗浄する。樹脂を次のカップリングサイクルの前に一定期間保持する場合、2回目のTFE/DCM洗浄液は排出せず、樹脂を当該TFE/DCM洗浄溶液中に保持する。
各カップリングサイクルを、各塩基含有サブユニットについて表3に初期C(シトシン)モノマーカップリングについて概説するように実施する。
最終カップリングステップを実施した後、樹脂を、それぞれ19.5LのIPAで8回洗浄し、真空下で室温で約63.5時間乾燥させて、乾燥重量を5,579.8gとする。
上記の樹脂結合PMO粗原薬を2ロットに分割し、各ロットを以下のように処理する。2,789.9gの樹脂のロットを、1)10LのNMPで2時間撹拌し、次いで、NMPを排出し、2)それぞれ10Lの30% TFE/DCMで3回洗浄し、3)10LのCYTFA溶液で15分間処理し、4)10LのCYTFA溶液で15分間処理し、次いでそれに130mLの1:1のNEM/DCMを添加し、2分間撹拌し、排出する。樹脂を、それぞれ10Lの中和溶液で3回処理し、10LのDCMで6回、およびそれぞれ10LのNMPで8回洗浄する。樹脂を、6.96LのNMP中の1530.4gのDTTおよび2980DBUの切断溶液で2時間処理し、PMO粗原薬を樹脂から切り離す。切断溶液を排出し、別個の槽に保持する。反応器および樹脂を、切断溶液と組み合わせた4.97LのNMPで洗浄する。
組み合わせた切断溶液とNMP洗浄液を圧力槽に移し、それに、冷凍庫内で−10℃〜−25℃の温度に予め冷却した39.8LのNH4OH(NH3・H2O)を添加した。圧力槽を密封し、45℃に16時間加熱し、次いで25℃に冷却させる。PMO粗原薬を含有するこの脱保護溶液を、精製水で3:1に希釈し、pHを2Mリン酸で3.0に、次いでNH4OHでpH8.03に調整する。
PMO粗原薬を含有する上記のパートDからの脱保護溶液を、ToyoPearl Super−Q 650Sアニオン交換樹脂(Tosoh Bioscience)のカラム上に装填し、17カラム体積に対して0〜35%Bの勾配で溶出し(緩衝液A:10mMの水酸化ナトリウム、緩衝液B:10mMの水酸化ナトリウム中の1Mの塩化ナトリウム)、許容される純度の画分(C18およびSCX HPLC)をプールして、精製された製剤溶液とする。
上述のPMO合成方法AまたはBプロトコルを使用して、以下の構造に従うPMOを合成し、
上述のプロトコルを使用して、以下の構造に従うPPMOを合成することができ、
ヒトジストロフィン(DMD)エクソン2、イントロン1、またはイントロン2を標的化するアンチセンスPMOオリゴマーを、横紋筋肉腫(RD)細胞におけるDMDエクソン2スキッピングについて評価した。
Claims (25)
- 前記塩基配列が、以下:配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号19、配列番号20、配列番号
21、配列番号25、配列番号26、配列番号27、配列番号28、または配列番号35のうちの1つから選択される、請求項1に記載の修飾アンチセンスオリゴマー。 - 前記塩基配列が、以下:配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号20、配列番号21、配列番号
25、配列番号26、配列番号27、配列番号28、または配列番号35のうちの1つから選択される、請求項1に記載の修飾アンチセンスオリゴマー。 - 前記塩基配列が、以下:配列番号3、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号20、配列番号21、配列番号25、配列番号26、配列番号27、または配列番号28のうちの1つから選択される、請求項1に記載の修飾アンチセンスオリゴマー。
- 前記塩基配列が、以下:配列番号6、配列番号7、配列番号25、または配列番号28のうちの1つから選択される、請求項1に記載の修飾アンチセンスオリゴマー。
- 前記塩基配列が、配列番号19である、請求項1に記載の修飾アンチセンスオリゴマー。
- 前記アニーリング部位の前記塩基配列が、配列番号37である、請求項1に記載の修飾アンチセンスオリゴマー。
- Tが、チミンである、請求項1〜10のいずれかに記載の修飾アンチセンスオリゴマー。
- 前記修飾アンチセンスオリゴマーの核酸塩基が、モルホリノ環構造に連結されている、請求項1〜11のいずれか一項に記載の修飾アンチセンスオリゴマー。
- 前記モルホリノ環構造が、1つの環構造のモルホリノ窒素を隣接する環構造の5’環外炭素に結合するリン含有サブユニット間連結によって結合される、請求項12に記載の修飾アンチセンスオリゴマー。
- 式(I)の1〜(n+1)個の各Nuが5’から3’に、以下:配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号19、配列番号20、配列番号21、配列番号25、配列番号26、配列番号
27、配列番号28、または配列番号35のうちの1つに対応する、請求項14に記載のアンチセンスオリゴマー。 - 式(I)の1〜(n+1)個の各Nuが5’から3’に、以下:配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号20、配列番号21、配列番号25、配列番号26、配列番号27、配列番号
28、または配列番号35のうちの1つに対応する、請求項14に記載のアンチセンスオリゴマー。 - 式(I)の1〜(n+1)個の各Nuが5’から3’に、以下:配列番号3、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号20、配列番号21、配列番号25、配列番号26、配列番号27、または配列番号28のうちの1つに対応する、請求項14に記載のアンチセンスオリゴマー。
- 式(I)の1〜(n+1)個の各Nuが5’から3’に、以下:配列番号6、配列番号7、配列番号25、または配列番号28のうちの1つに対応する、請求項14に記載のアンチセンスオリゴマー。
- 式(I)の1〜(n+1)個の各Nuが5’から3’に、配列番号19の前記核酸塩基に対応する、請求項14に記載のアンチセンスオリゴマー。
- 式(I)の1〜(n+1)個の各Nuが5’から3’に、配列番号37の前記核酸塩基に対応する、請求項14に記載のアンチセンスオリゴマー。
- Tが、チミンである、請求項14〜23のいずれか一項に記載のアンチセンスオリゴマー。
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