JP6259029B2 - ナトリウムチャネル、電位依存性、αサブユニット(SCNA)に対する天然アンチセンス転写物の阻害によるSCNA関連疾患の治療 - Google Patents
ナトリウムチャネル、電位依存性、αサブユニット(SCNA)に対する天然アンチセンス転写物の阻害によるSCNA関連疾患の治療 Download PDFInfo
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Description
本出願は、2010年6月23日に提出された米国仮特許出願第61/357,774号の優先権を主張し、当該米国仮特許出願は、参照によりその全内容が本明細書に組み込まれる。
本明細書で使用される用語の選択は、特定の実施形態を説明する目的でされたものであり、本発明を限定することを意図するものではない。本明細書で使用される場合、単数形の「a」、「an」、及び「the」は文脈において明らかに別記されない限り、複数形の内容も含むものとする。さらに、用語「含む」、「含める」、「有する」、「もつ」またはその変化形は、本明細書および/または添付の請求項において使用される場合、用語「包含する」と同様に非排他的な意味で用いられるものとする。
SNPの存在は、例えば、易罹患性対抵抗性である病態についてのある傾向を有する特定の集団についての指標であり得る。
頭痛、昏迷および昏睡、認知症、てんかん、睡眠障害、心的外傷、感染症、腫瘍、神経眼科学、運動障害、脱髄性疾患、脊髄障害、および末梢神経、筋肉および神経筋接合部の障害が挙げられる。さらに、中毒および精神疾患として、以下に限定されるものではないが、双極性障害および統合失調症が、同様に、神経障害の定義にて含まれる。本発明による組成物および方法を使用して処置され得るいくつかの神経障害、症状、兆候および症候群の一覧を以下に記載する。
神経疾患の例は、以下に限定されるものではないが、後天性てんかん性失語症、急性散在性脳脊髄炎、副腎白質ジストロフィー、加齢黄斑変性症、脳梁欠損症、失認症、アイカルディ症候群、アレクサンダー病、アルパース病、交代性片麻痺、脳血管性痴呆、筋萎縮性側索硬化症、無脳症、アンジェルマン症候群、血管腫症、無酸素症、失語症、失行症、くも膜嚢胞、くも膜炎、アーノルド・キアリ奇形、動静脈奇形、アスペルガー症候群、毛細血管拡張性運動失調症、注意欠陥多動性障害、自閉症、自律神経機能障害、背中の痛み、バッテン病、ベーチェット病、ベル麻痺、良性特発性眼瞼けいれん、良性限局性異常、筋萎縮症、良性頭蓋内圧亢進症、ビンスワンガー病、眼瞼けいれん、ブロッホ・サルズバーガー症候群、腕神経叢損傷、脳膿瘍、脳損傷、脳腫瘍(多形性膠芽腫を含む)、脊髄腫瘍、ブラウンセカール症候群、カナバン病、手根管症候群、カウザルギー、中枢性疼痛症候群、橋中心髄鞘崩壊、頭部の障害、脳動脈瘤、脳動脈硬化症、萎縮脳、脳性巨人症、脳性麻痺、シャルコー・マリー・トゥース病、化学療法誘発性神経障害と神経因性疼痛、キアリ奇形、舞踏病、慢性炎症性脱髄性多発神経障害、慢性疼痛、慢性局所疼痛症候群、コフィンローリー症候群、遷延性植物状態を含む昏睡状態、先天性顔面麻痺、大脳皮質基底核変性症、頭蓋の動脈炎、頭蓋骨早期癒合症、クロイツフェルト・ヤコブ病、蓄積外傷疾患、クッシング症候群、巨大細胞性封入体症、サイトメガロウイルス感染症、ダンシングアイズ・ダンシングフィート症候群(眼球クローヌス・ミオクローヌス運動失調)、ダンディ・ウォーカー症候群、ドーソン病、ド・モルシア症候群、デジェリン−クルムプケ麻痺、認知症、皮膚筋炎、糖尿病性神経障害、びまん性硬化症、自律神経障害、書字障害、失読症、ジストニア、早期乳児てんかん性脳症、エンプティセラ症候群、脳炎、脳瘤、脳三叉神経領域血管腫症、てんかん、エルブ麻痺、本態性振戦、ファブリー病、ファール症候群、失神、家族性けいれん性麻痺、熱性けいれん、フィッシャー症候群、フリードライヒ失調症、前頭側頭認知症およびその他の「タウオパチー」、ゴーシェ病、ゲルストマン症候群、巨細胞性動脈炎、巨細胞性封入体病、球様細胞白質萎縮症、ギラン・バレー症候群、HTLV−1関連脊髄症、ハレルフォルデンスパッツ病、頭部外傷、頭痛、片側顔面けいれん、遺伝性痙性対麻痺、遺伝性多発神経炎性失調、耳帯状疱疹、帯状疱疹、平山病、HIV関連認知症および神経障害(AIDSの神経学的症状も)、全前脳症、ハンチントン病および他のポリグルタミンリピート病、水無脳症、水頭症、副腎皮質機能亢進症、低酸素症、免疫介在性脳脊髄炎、封入体筋炎、色素失調症、幼児型フィタン酸蓄積症、乳児型レフサム病、乳児痙攣、炎症性筋疾患、頭蓋内の嚢胞、頭蓋内圧亢進、ジュベール症候群、カーンズ・セイヤー症候、ケネディ病、キンズボーン症候群、クリッペル・ファイル症候群、クラッベ病、クーゲル・ウエランダー病、クールー、ラフォラ病、ランバート・イートン症候群、ランドウ・クレフナー症候群、外側延髄(ウォレンバーグ)症候群、学習障害、リー病、レノックス・ガストー症候群、レッシュナイハン症候群、大脳白質萎縮症、レビー小体型認知症、滑脳症、閉じ込め症候群、ルー・ゲーリッグ病(すなわち運動ニューロン疾患または筋萎縮性側索硬化症)、腰椎椎間板疾患、ライム病−神経学的後遺症、マチャド・ジョセフ病、大脳症、巨大脳髄症、メルカーソン・ローゼンタール症候群、メニエール病、髄膜炎、メンケス病、異染性白質ジストロフィー、小頭症、片頭痛、ミラーフィッシャー症候群、軽度の脳卒中、ミトコンドリアミオパシー、メビウス症候群、モノマー性筋萎縮症、運動ニューロン疾患、もやもや病、ムコ多糖症、多発梗塞性痴呆、多巣性運動ニューロパチー、多発性硬化症および他の脱髄性疾患、起立性低血圧を伴う多系統萎縮症、筋ジストロフィー、重症筋無力症、ミエリン代謝異常によるびまん性硬化症、乳児型ミオクロニー脳症、ミオクローヌス、筋疾患、先天性ミオトニア、ナルコレプシー、神経線維腫症、悪性症候群、AIDSの神経学的症状、紅斑性狼瘡の神経学的後遺症、神経性筋緊張病、神経セロイドリポフスチン症、神経細胞遊走障害、ニーマン・ピック病、オサリバン・マクラウド症候群、後頭神経痛、潜在性脊椎閉鎖不全症、大田原症候群、オリーブ橋小脳萎縮症、オプソクローヌス・ミオクローヌス症候群、視神経炎、起立性低血圧、使い過ぎ症候群、感覚異常、神経変性疾患または障害(パーキンソン病、ハンチントン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、認知症、多発性硬化症、および神経細胞死に関連する他の疾患および障害)、先天性パラミオトニア、腫瘍随伴性疾患、発作、パリーロンベルク症候群、ペリツェウスメルツバッハー病、周期性麻痺、末梢神経障害、痛みを伴う神経障害および神経因性疼痛、遷延性植物状態、広汎性発達障害、光くしゃみ反射、フィタン酸蓄積症、ピック病、挟まれた神経、下垂体腫瘍、多発性筋炎、孔脳症、ポリオ後症候群、帯状疱疹後神経痛、感染後脳脊髄炎、起立性低血圧、プラダーウィリ症候群、原発性側索硬化症、プリオン病、進行性顔面半側萎縮症、進行性多巣性白質脳症、進行性硬化性ポリオジストロフィー、進行性核上性麻痺、偽脳腫瘍、ラムゼイ・ハント症候群(I型およびII型)、ラスムッセン脳炎、反射性交感神経性ジストロフィー症候群、レフサム病、反復運動障害、反復ストレス障害、むずむず脚症候群、レトロウイルス関連脊髄症、レット症候群、ライ症候群、舞踏病、サンドホフ病、シルダー病、裂脳症、中隔視神経異形成症、揺さぶられっ子症候群、帯状疱疹、シャイ・ドレーガー症候群、シェーグレン症候群、睡眠時無呼吸症候群、ソトス症候群、痙縮、二分脊椎、脊髄損傷、脊髄腫瘍、脊髄性筋萎縮症、スティッフパーソン症候群、脳卒中、スタージ・ウェーバー症候群、亜急性硬化性全脳炎、皮質下動脈硬化性脳症、シデナム舞踏病、失神、脊髄空洞症、遅発性ジスキネジア、テイ・サックス病、側頭動脈炎、係留脊髄症候群、トムセン病、胸郭出口症候群、疼痛チック、トッドの麻痺、トゥレット症候群、一過性脳虚血発作、伝達性海綿状脳症、横断性脊髄炎、外傷性脳損傷、振戦、三叉神経神経痛、熱帯性痙性不全対麻痺、結節性硬化症、血管性痴呆(多発梗塞性痴呆)、側頭動脈炎を含む脈管炎、フォンヒッペル・リンドウ病、ウォレンバーグ症候群、ウェルドニッヒ・ホフマン病、ウエスト症候群、むち打ち症、ウィリアムズ症候群、ウィルソン病、およびゼルウィガー症候群が挙げられる。
表2:SCN1Aに特異的な天然のアンチセンス転写物を標的にするアンチセンスオリゴヌクレオチドで処置された細胞内のSCN1AのmRNAの相対的な発現。平均(Avg)−偽トランスフェクト対照と比較したSCN1A発現での平均の倍差;標準偏差(Std)−標準偏差、P−治療されたサンプルが偽対照とは異ならない可能性。反復数(N)−反復数
Tmが高くなるほど、標的に対するオリゴヌクレオチドの親和性は大きい。
、CH2−O−N(CH3)−CH2、CH2−N(CH3)−−N(CH3)−CH2およびO−N(CH3)−CH2−CH2骨格、式中天然のホスホジエステル骨格はO−P−O−CHと表される)を有するものである。De Mesmaekerら(1995)Acc.Chem.Res.28:366−374)によって開示されたアミド骨格も好ましい。同様に好ましいのは、モルホリノ骨格構造を有するオリゴヌクレオチドである(SummertonおよびWeller、米国特許第5,034,506号)。他の好ましい実施形態において、ペプチド核酸(PNA)骨格、オリゴヌクレオチドのホスホジエステル骨格などは、ポリアミド骨格で置換され、ヌクレオチドは直接または間接的にポリアミド骨格のアザ窒素原子に結合される。オリゴヌクレオチドは、1以上の置換された糖部分も含み得る。好ましいオリゴヌクレオチドは、以下のもの:OH、SH、SCH3、F、OCN、OCH3OCH3、OCH3O(CH2)nCH3、O(CH2)nNH2またはO(CH2)nCH3(nは1〜約10);C1〜C10低級アルキル、アルコキシアルコキシ、置換された低級アルキル、アルカリルまたはアラルキル;Cl;Br;CN;CF3;OCF3;O−、S−、またはN−アルキル;O−、S−、またはN−アルケニル;SOCH3;SO2;CH3;ONO2;NO2;N3;NH2;ヘテロシクロアルキル;ヘテロシクロアルカリル;アミノアルキルアミノ;ポリアルキルアミノ;置換されたシリル;RNA切断基;レポーター基;干渉物質;オリゴヌクレオチドの薬物動態特性を改善する基;またはオリゴヌクレオチドの薬力学特性を改善する基および同様の特性を有する他の置換基のうちの1つを2’位置に含む。好ましい修飾は、2’−メトキシエトキシ[2’−O−CH2CH2OCH3、2’−O−(2−メトキシエチル)としても周知]を含む。他の好ましい修飾は2’−メトキシ(2’−O−CH3)、2’−プロポキシ(2’−OCH2CH2CH3)および2’−フルオロ(2’−F)を含む。同様に修飾は、オリゴヌクレオチドの他の位置、詳細には3’末端ヌクレオチドの糖の3’位および5’末端ヌクレオチドの5’位でも作製され得る。オリゴヌクレオチドは、ペントフラノシル基の代わりにシクロブチルなどの糖類似体も有し得る。
外来性核酸の宿主細胞または生体内への輸送は、細胞中または生体中の核酸を直接検出するステップによって評価され得る。そのような検出は、当技術分野において周知のいくつかの方法によって達成し得る。例えば、外来性核酸の存在は、サザンブロットまたは核酸に関連するヌクレオチド配列を特異的に増幅するプライマーを使用するポリメラーゼ連鎖反応(PCR)技術によって検出し得る。外来性核酸の発現も遺伝子発現分析を含む従来の方法を使用して測定し得る。例えば外来性核酸から生成されるmRNAはノーザンブロットおよび逆転写PCR(RT−PCR)を使用して検出および定量し得る。
本発明の化合物は、診断、治療および予防のためにならびに研究用試薬およびキットの構成要素として利用され得る。さらに、優れた特異性をもって遺伝子発現を阻害できるアンチセンスオリゴヌクレオチドは、当業者によって特定の遺伝子の機能を解明するため、または生物学的経路の種々のメンバー間の機能を区別するために使用されることが多い。
本発明のオリゴヌクレオチドの他の修飾は、オリゴヌクレオチドの活性、細胞分布または細胞への取り込みを増強する1以上の成分またはコンジュゲートへのオリゴヌクレオチドの化学的連結を含む。これらの成分またはコンジュゲートは、1級または2級ヒドロキシル基などの官能基に共有結合したコンジュゲート基を含み得る。本発明のコンジュゲート基は、干渉物質、レポーター分子、ポリアミン、ポリアミド、ポリエチレングリコール、ポリエーテル、オリゴマーの薬力学特性を増強する基、およびオリゴマーの薬物動態特性を増強する基を含む。典型的なコンジュゲート基は、コレステロール、脂質、リン脂質、ビオチン、フェナジン、葉酸、フェナントリジン、アントラキノン、アクリジン、フルオレセイン、ローダミン、クマリン、および色素を含む。本発明の文脈において薬力学特性を増強する基は、取り込みを改善し、分解への耐性を増強し、および/または標的核酸との配列特異的ハイブリダイゼーションを強化する基を含む。本発明の文脈において薬物動態特性を増強する基は、本発明の化合物の取り込み、分散、代謝または排出を改善する基を含む。代表的コンジュゲート基は、1992年10月23日出願の国際特許出願PCT/US92/09196および米国特許第6,287,860号、「Antisense inhibition of MEKK2 expression」において開示されており、これらはともに参照により本明細書に組み込まれる。コンジュゲート成分は、以下に限定されないが、コレステロール成分、コール酸、チオエーテル(例えばヘキシル−S−トリチルチオール)、チオコレステロール、脂肪族鎖(例えばドデカンジオールまたはウンデシル残基)、リン脂質(例えばジ−ヘキサデシル−rac−グリセロールまたはトリエチルアンモニウム1,2−ジ−O−ヘキサデシル−rac−グリセロ−3−H−ホスホネート)、ポリアミンまたはポリエチレングリコール鎖、あるいはアダマンタン酢酸、パルミチル成分、またはオクタデシルアミンもしくはヘキシルアミノ−カルボニル−オキシコレステロール成分などを含む。本発明のオリゴヌクレオチドは、活性原薬、例えばアスピリン、ワルファリン、フェニルブタゾン、イブプロフェン、スプロフェン、フェンブフェン、ケトプロフェン、(S)−(+)−プラノプロフェン、カプロフェン、ダンシルサルコシン、2,3,5−トリヨード安息香酸、フルフェナム酸、フォリン酸、ベンゾチアジアジド、クロロチアジド、ジアセピン、インドメチシン、バルビツール酸、セファロスポリン、サルファ剤、抗糖尿病薬、抗菌剤または抗生物質ともコンジュゲート形成され得る。
本発明の化合物は、取り込み、分散および/または吸収の補助に、例えばリポソーム、受容体−標的分子、経口、直腸、局所または他の製剤として、他の分子、分子構造または化合物と、混合物と混合、封入、コンジュゲート化または他の方法で結合され得る。そのような取り込み、分散および/または吸収を補助する製剤の調製について記載した代表的米国特許としては、以下に限定されないが、米国特許第5,108,921号;第5,354,844号;第5,416,016号;第5,459,127号;第5,521,291号;第5,543,165号;第5,547,932号;第5,583,020号;第5,591,721号;第4,426,330号;第4,534,899号;第5,013,556号;第5,108,921号;第5,213,804号;第5,227,170号;第5,264,221号;第5,356,633号;第5,395,619号;第5,416,016号;第5,417,978号;第5,462,854号;第5,469,854号;第5,512,295号;第5,527,528号;第5,534,259号;第5,543,152号;第5,556,948号;第5,580,575号;および第5,595,756号が挙げられ、それぞれが本明細書に参照として組み込まれる。
DNAウイルス性ベクターが好ましい。これらのベクターには、オルソポックスベクターまたはトリポックスベクターなどのポックスベクター、単純ヘルペスIウイルス(HSV)ベクターなどのヘルペスウイルスベクター、アデノウイルスベクター、およびアデノ関連ウイルスベクターが含まれる。
pH感受性または負に荷電したリポソームは、複合体化するよりもDNAを捕捉すると考えられる。カチオン性および非カチオン性の両方のリポソームは、DNAを細胞に送達するために使用されている。
治療用組成物の処方およびそれらの続く投与(投薬)は、当業者の技能の範囲内であると考えられる。投薬は、数日間から数カ月間継続する、または治療が効果的になるかもしくは病態の減退が達成されるまでの治療過程において、治療される病態の重症度および応答性に応じて決まる。最適な投薬レジメンは、患者の身体での薬剤蓄積の測定値から算出され得る。当業者であれば、最適投与量、投薬方法および反復頻度を容易に決定できる。最適な投与量は、個々のオリゴヌクレオチドの相対的効力に応じて変動し得、通常体外および生体内動物モデルにおいて効果的であると判明したEC50に基づいて推定され得る。通常投与量は、体重1kgあたり0.01μg〜100gであり、1日に、1週間に、1カ月にもしくは1年に1回もしくは複数回またはさらに2〜20年ごとに1回である場合がある。当業者であれば、測定された滞留時間および体液または組織における薬剤の濃度に基づいて投薬の反復頻度を容易に推定できる。治療の成功に続いて、病態の再発を予防するために患者に維持療法を受けさせることが望ましい場合があり、ここでオリゴヌクレオチドは維持投与において体重1kgあたり0.01μg〜100g、1日1回または複数回から20年ごとに1回の範囲で投与される。
以下の限定を意図しない実施例は、本発明の選択された実施形態を例示するものである。提示される構成部分の要素の割合を変えることや代替物は当業者に明らかであり、本発明の実施形態の範囲内であることは理解されよう。
SCN1Aに特異的な天然のアンチセンス転写物の機能の調節によるSCN1AのmRNA/タンパク質のアップレギュレーションは、単一のオリゴヌクレオチド、組織または種に限定的でなく、つまり一般の事象であることが下記のデータにより確認される。
DNAse/RNAseフリーの滅菌水に20μΜの濃度でオリゴヌクレオチドの貯蔵液を希釈した。1ウエルに投与するため、この溶液2μlをOptiMEM培地(Gibco cat#31985−070)400μlおよびLipofectamine 2000(Invitrogen cat#11668019)4μlと室温で20分間インキュベートし、細胞を含む6穴プレートの1ウエルに液滴で添加した。該オリゴヌクレオチド溶液の代わりに水2μlを含む同様の混合物を偽トランスフェクト対照に使用した。さらに、対照として同一濃度の不活性オリゴヌクレオチドCUR−1462を使用した。37℃、5% CO2での18時間のインキュベーション後、培地を新鮮な前述の増殖培地に交換した。アンチセンスオリゴヌクレオチドの添加の48時間後、培地を除去し、Promega製のSV Total RNA Isolation System(cat #Z3105)を製造者の説明書に従って使用して、RNAを細胞から抽出した。600ngの全精製RNAを、Invitrogen製のSuperscript VILO cDNA合成キット(cat#11754ー250)を製造者の説明書に記載のとおり使用して実施した逆転写反応に加えた。この逆転写反応からのcDNAを使用して、ABI Taqman gene Expression Mix(cat#4369510)およびABI(ヒトSCNA用Hs00374696_m1、Hs00897350_m1、またはHs00897341_m1アッセイ)によって設計されたプライマープローブを使用するリアルタイムPCRによって遺伝子発現をモニタリングした。3つのアッセイをすべて使用して得られた結果は大変似通っていた。使用したPCRサイクルは次の通り:50℃で2分間、95℃で10分間、(95℃で15秒間、60℃で1分間)を40サイクル、StepOne Plus Real Time PCR system(Applied Biosystems)を使用。18Sに対するアッセイはABI製(cat#4319413E)であった。アンチセンスオリゴヌクレオチドで処置した後の遺伝子発現の変化率を、処置サンプルと偽トランスフェクトサンプルの間の18S標準化dCt値の差に基づいて計算した。もう一方の同日法では、手順はすべて同様に実施されたが、初日に細胞を6穴プレートに播種した直後にアンチセンスオリゴヌクレオチドを投与した。
結果:用量応答実験の結果により、SCN1Aに特異的な天然のアンチセンスRNAを標的とするアンチセンスオリゴヌクレオチドがSCN1AのmRNAの用量依存性のアップレギュレーションを引き起こせることが確認された(図1−3)。一部の場合において、このアップレギュレーションは高用量で大変顕著であった(最高60倍)(図1−3)。異種細胞株において同一のヌクレオチドにより引き起こされたアップレギュレーションの程度は、異なるようであり、例えば、40nMで初代線維芽細胞において達成されたアップレギュレーションは、10−40倍のレベルであったが、同一濃度、同一オリゴヌクレオチドによるVero76細胞内のアップレギュレーションは、2−6倍であった(図1対図3)。これらの差は異種細胞株で導入効率が異なること、またはこれら細胞により発現された多様なフィードバック経路が原因であろう。ほとんどのオリゴヌクレオチドの効果は約40nMでプラトーに到達したが、SCN1A繊維芽細胞におけるCUR−1764およびCUR−1770、およびVero76細胞において検査されたすべてのオリゴヌクレオチドは例外であり、テストした最高濃度でプラトーに到達しなかった。
レベルをELISAにより定量化することであった。
BG724147に特異的なプライマーを使用した類似のサイズのバンドの増幅により、両細胞型においてBG724147の存在が確認された。
Claims (17)
- 生物学的な系におけるナトリウムチャネル、電位依存性、I型、αサブユニット(SCN1A)ポリヌクレオチドの機能および/もしくは発現をアップレギュレートする方法において使用するためのアンチセンスオリゴヌクレオチドであって、
前記方法は、前記系を前記アンチセンスオリゴヌクレオチドと接触させることを含み、それにより、SCN1Aポリヌクレオチドの機能および/もしくは発現をアップレギュレートし、
前記アンチセンスオリゴヌクレオチドは、配列番号29、37、40、50、51、56、61、67、78、82、84、85、90、91または92に示される配列を有する、
アンチセンスオリゴヌクレオチド。 - 前記アンチセンスオリゴヌクレオチドが、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオシド間結合、少なくとも1つの修飾ヌクレオチド、およびそれらの組み合わせから選択された1以上の修飾を含む、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾が、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された、少なくとも1つの修飾糖部分を含む、請求項2に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾は、ホスホロチオアート、2’−O−メトキシエチル(MOE)、2’−フルオロ、アルキルホスホナート、ホスホロジチオエート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオシド間結合を含む、請求項2に記載のアンチセンスオリゴヌクレオチド。
- 前記1以上の修飾が、ペプチド核酸(PNA)、ロックト核酸(LNA)、アラビノ核酸(FANA)、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオチドを含む、請求項2に記載のアンチセンスオリゴヌクレオチド。
- in vivoまたはin vitroで哺乳動物の細胞または組織におけるナトリウムチャネル、電位依存性、I型、αサブユニット(SCN1A)遺伝子の機能および/または発現をアップレギュレートする方法において使用するための低分子干渉RNA(siRNA)オリゴヌクレオチドであって、
前記方法は、前記細胞または組織を前記siRNAオリゴヌクレオチドと接触させることと、in vivoまたはin vitroで哺乳動物の細胞または組織におけるSCN1Aの機能および/または発現をアップレギュレートすることと、を含み、
前記siRNAオリゴヌクレオチドは、配列番号29、37、40、50、51、56、61、67、78、82、84、85、90、91または92に示される配列を有する、
低分子干渉RNA(siRNA)オリゴヌクレオチド。 - 少なくとも1つの修飾を含む合成された修飾オリゴヌクレオチドであって、
前記少なくとも1つの修飾が、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオチド間結合、少なくとも1つの修飾ヌクレオチド、およびそれらの組み合わせから選択されたものであり、
前記オリゴヌクレオチドは、配列番号29、37、40、50、51、56、61、67、78、82、84、85、90、91または92に示される配列を有し、通常の対照と比較してナトリウムチャネル、電位依存性、I型、αサブユニット(SCN1A)遺伝子の機能および/または発現をアップレギュレートする、
オリゴヌクレオチド。 - 前記少なくとも1つの修飾は、ホスホロチオアート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択されたヌクレオチド間結合を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、少なくとも1つのホスホロチオアートヌクレオチド間結合を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、ホスホロチオアートヌクレオチド間結合の骨格を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、少なくとも1つの修飾されたヌクレオチドを含み、前記修飾されたヌクレオチドは、ペプチド核酸、ロックト核酸(LNA)、およびそれらの組み合わせから選択されたものである、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、複数の修飾を含み、前記修飾は、ホスホロチオアート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホラミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、複数の修飾を含み、前記修飾は、ペプチド核酸、ロックト核酸(LNA)、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された、少なくとも1つの修飾糖部分を含む、請求項7に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、複数の修飾を含み、前記修飾は、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された修飾糖部分を含む、請求項7に記載のオリゴヌクレオチド。
- 1種以上の請求項1〜15のいずれか1項に記載のオリゴヌクレオチドと、薬学的に許容される賦形剤と、を含む医薬組成物。
- 少なくとも1つのナトリウムチャネル、電位依存性、I型、αサブユニット(SCN1A)ポリヌクレオチドおよび/または少なくとも1つのそのコードされた生成物に関連する疾病を予防または治療する方法において使用するための、請求項1〜15のいずれか1項に記載のオリゴヌクレオチドであって、
前記方法は、患者に対し、前記オリゴヌクレオチドを治療上有効な用量で投与することを含み、それによって、前記少なくとも1つのナトリウムチャネル、電位依存性、I型、αサブユニット(SCN1A)ポリヌクレオチドおよび/または少なくとも1つのそのコードされた生成物に関連する疾病を予防または治療し、
前記疾病が、SCN1Aの異常な機能および/または発現に関連した疾患または障害、神経疾患または障害、ひきつけ、疼痛、慢性疼痛、ナトリウムチャネル障害に関わる電気興奮性の障害、ナトリウムチャネル障害に関連した疾患または障害、電位依存性ナトリウムチャネルαサブユニット活性の誤制御に関連した疾患または障害、麻痺、高カリウム性周期性四肢麻痺、先天性筋緊張症、カリウム惹起性ミオトニー、長QT間隔症候群3、運動終板疾患、失調症、腸神経系の障害による胃腸管疾患、結腸炎、回腸炎、起炎性腸症候群、心血管系疾患または障害、高血圧症、うっ血性心不全、交感および副交感神経支配に関わる尿生殖路の疾患または障害、良性前立腺肥大症、性交不能症、筋神経系に関連した疾患または障害、筋ジストロフィー症、多発硬化症、てんかん、自閉症、偏頭痛、孤発性偏頭痛、家族性片麻痺性偏頭痛、乳児期の重度ミオクローヌス性てんかん(SMEI)、全般てんかん熱性けいれんプラス(GEFS+)およびSCNA関連のてんかん障害から選択される、
オリゴヌクレオチド。
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