JP2013502224A - ‘hsp70相互作用タンパク質c末端’(chip)に対する天然アンチセンス転写産物の阻害によるchip関連疾患の治療 - Google Patents
‘hsp70相互作用タンパク質c末端’(chip)に対する天然アンチセンス転写産物の阻害によるchip関連疾患の治療 Download PDFInfo
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Abstract
Description
配列番号1:ホモ・サピエンス(Homo sapiens)STIP1相同体およびU−ボックス含有タンパク質1(STUB1)、mRNA(NCBIアクセッション番号:NM_005861);配列番号2:天然CHIPアンチセンス配列(Hs.533771);配列番号3:天然CHIPアンチセンス配列(BX088969);配列番号4〜11:アンチセンスオリゴヌクレオチド。*はホスホチオアート結合を表し、「r」はRNAを表す。
本明細書で使用される用語は、単に特定の実施形態を説明することを目的とし、本発明の限定を意図するものではない。本明細書で使用される単数形「a」、「an」および「the」は、文脈により別途明示されない限り、複数形も包含する。さらに、「含む(including)」、「含む(includes)」、「有する(having)」、「有する(has)」、「有する(with)」またはその変化形が、詳細な説明および/または特許請求の範囲において使用され使用される限り、これらの用語は「含む(comprising)」という用語と同様に包含的であることが意図される。
標的:一実施形態では、標的は、‘HSP70相互作用タンパク質C末端’(CHIP)に関連したセンスおよび/またはアンチセンスの非コードおよび/またはコード配列を非限定的に含むCHIPの核酸配列を含む。
外来核酸の宿主細胞または生物体内への移入は、細胞または生物体中の核酸の存在を直接検出することにより評価し得る。このような検出は、当該技術分野で公知のいくつかの方法により達成し得る。例えば、外来核酸の存在を、サザンブロット法により、またはその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用いたポリメラーゼ連鎖反応(PCR)技術により検出し得る。外来核酸の発現も、遺伝子発現解析を含めた従来の方法を用いて測定し得る。例えば、外来核酸から生成されたmRNAを、ノーザンブロット法および逆転写PCR(RT−PCR)を用いて検出および定量化し得る。
本発明の化合物は、診断、治療および予防に、ならびに研究試薬およびキットの成分として使用し得る。さらに、優れた特異性で遺伝子発現を阻害することができるアンチセンスオリゴヌクレオチドは多くの場合、特定の遺伝子の機能を明らかにするために、または生物学的経路の様々なメンバーの機能を区別するために、当業者により使用される。
本発明のオリゴヌクレオチドの別の修飾は、オリゴヌクレオチドの活性、細胞内分布または細胞内取り込みを増大させる1つ以上の部分またはコンジュゲートをオリゴヌクレオチドと化学的に結合させることを含む。これらの部分またはコンジュゲートは、第一級または第二級ヒドロキシル基のような官能基と共有結合しているコンジュゲート基を含む。本発明コンジュゲート基としては、インターカレーター、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的特性を増強する基が挙げられる。典型的なコンジュゲート基としては、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が挙げられる。本発明との関連において、薬力学特性を増強する基は、取り込みを向上させる、分解に対する耐性を増強するおよび/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。本発明との関連において、薬物動態的を増強する基は、本発明の化合物の取り込み、分布、代謝または排泄を向上させる基を含む。代表的なコンジュゲート基は、参照により本明細書に組み込まれる、1992年10月23日に出願された国際出願PCT/US92/09196号および米国特許第6,287,860号に開示されている。コンジュゲート部分としては、脂質部分、例えばコレステロール部分、コール酸、チオエーテル(例えば、ヘキシル−5−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1,2−ジ−O−ヘキサデシル−rac−グリセロ−3−Hホスホン酸トリエチルアンモニウム)、ポリアミンもしくはポリエチレングリコール鎖、またはアダマンタン酢酸、パルミチル部分、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部分などが挙げられるが、これらに限定されない。また本発明のオリゴヌクレオチドは、活性な原薬、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、カルプロフェン、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、ホリン酸、ベンゾチアジアジド、クロロチアジド、ジアゼピン、インドメチシン(indomethicin)、バルビツール酸、セファロスポリン、サルファ剤、抗糖尿病剤、抗菌剤または抗生物質とコンジュゲートし得る。
また本発明の化合物は、取り込み、分布および/または吸収を補助するための、例えば(forexample)、リポソーム、受容体標的化分子、経口、口腔、直腸内、局所またはその他の製剤として、他の分子、分子構造または化合物の混合物と混合するか、封入するか、コンジュゲートするかまたはその他の方法で一緒にし得る。このような取り込み、分布および/または吸収を補助する製剤の調製を教示する代表的な米国特許としては、それぞれ参照により本明細書に組み込まれる、米国特許第5,108,921号;同第5,354,844号;同第5,416,016号;同第5,459,127号;同第5,521,291号;同第5,543,165号;同第5,547,932号;同第5,583,020号;同第5,591,721号;同第4,426,330号;同第4,534,899号;同第5,013,556号;同第5,108,921号;同第5,213,804号;同第5,227,170号;同第5,264,221号;同第5,356,633号;同第5,395,619号;同第5,416,016号;同第5,417,978号;同第5,462,854号;同第5,469,854号;同第5,512,295号;同第5,527,528号;同第5,534,259号;同第5,543,152号;同第5,556,948号;同第5,580,575号;および同第5,595,756号が挙げられるが、これらに限定されない。
治療用組成物の製剤化およびそれに続く投与(投薬)は、当業者の技術の範囲内にあると考えられる。投薬は、治療される病的状態の重症度および応答性によって決まり、治療過程は数日〜数ヶ月、または治癒がもたらされるか、もしくは病的状態の減退が達成されるまで続く。最適な投薬計画は、患者体内の薬物蓄積の測定から計算し得る。当業者は、最適用量、投薬方法および反復速度を容易に決定することができる。最適用量は、個々のオリゴヌクレオチドの相対的効力によって異なり得るが、一般的には、インビトロおよびインビボ動物モデルにおいて効果的であることがわかるEC50に基づき推定することができる。一般に用量は、体重1kg当たり0.01μg〜100gであり、また1日、1週間、1ヶ月もしくは1年に1回以上、または2〜20年に1回投与し得る。当業者は、体液または組織中において測定された薬物の滞留時間および濃度に基づき、投薬の反復速度を容易に推定することができる。良好な治療の後、病的状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、この場合、オリゴヌクレオチドを、1日1回以上〜20年に1回、体重1kg当たり0.01μg〜100gの範囲の維持投与量で投与する。
上記の通り、「〜に特異的なオリゴヌクレオチド」または「オリゴヌクレオチドは〜を標的とする」という用語は、(i)標的遺伝子の一部分と安定な複合体を形成することができる、または(ii)標的遺伝子のmRNA転写産物の一部分と安定な二重鎖を形成することができる配列を有する、オリゴヌクレオチドを指す。
アンチセンスオリゴヌクレオチドによるZR75−1細胞の処置
1.zr−75細胞をRPMI(ATCC番号30−2001)+10%FBS+ペニシリン+ストレプトマイシン中、37℃および5%CO2で増殖させた。実験の1日前に、細胞を6ウェルプレート中に1.5×105/mlの密度で再び播き、37℃および5%CO2でインキュベートした。実験日に、6ウェルプレート中の培地を新たな増殖培地に交換した。すべてのアンチセンスオリゴヌクレオチドを20μMの濃度まで希釈した。この溶液2μlを、400μlのOpti−MEM培地(Gibco、カタログ番号31985−070)および4μlのリポフェクタミン2000(Invitrogen、カタログ番号11668019)と共に、室温で20分間インキュベートし、ZR75−1細胞を含む6ウェルプレートの各ウェルに加えた。オリゴヌクレオチド溶液の代わりに2μlの水を含む同様の混合物を擬似トランスフェクト対照に使用した。37℃および5%CO2で3〜18時間インキュベートした後、培地を新たな増殖培地に交換した。アンチセンスオリゴヌクレオチド添加の48時間後に、培地を除去し、Promega製のSV Total RNA Isolation System(カタログ番号Z3105)またはQiagen製のRNeasy Total RNA Isolationキット(カタログ番号74181)を製造者の説明書に従って用い、細胞からRNAを抽出した。Thermo Scientific製のVerso cDNAキット(カタログ番号AB1453B)またはHigh Capacity cDNA Reverse Transcription Kit(カタログ番号4368813)を製造者プロトコールに記載されている通りに用いて行う逆転写反応に、600ngのRNAを加えた。この逆転写反応から得られたcDNAを用いて、ABI Taqman Gene Expression Mix(カタログ番号4369510)およびABIにより設計されたプライマー/プローブ(Applied Biosystems Inc.、Foster City CAによるApplied Biosystems Taqman Gene Expression Assay:Hs00195300_m1)を用いたリアルタイムPCRにより遺伝子発現をモニターした。以下のPCRサイクルを使用した:Mx4000サーマルサイクラー(Stratagene)を用いて、50℃で2分間、95℃で10分間、(90℃で15秒間、60℃で1分間)の40サイクル。アンチセンスオリゴヌクレオチドによる処置後の遺伝子発現の倍数変化を、処置試料および擬似トランスフェクト試料の間の18S正規化したdCt値の差に基づいて計算した。
リアルタイムPCRの結果は、ZR75−1細胞中のCHIP1 mRNAのレベルが、BX088969.1に対して設計されたsiRNAのうちの2つ(CUR−0314およびCUR−0316)による処置の48時間後に有意に増加することを示している。Hs.5337715に対して設計された3つのホスホロチオアートアンチセンスオリゴ(CUR−0879〜CUR−0883)もCHIP1 mRNAレベルを有意に上方制御した(図1)。
Claims (37)
- 患者細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、少なくとも1つの5〜30ヌクレオチド長のアンチセンスオリゴヌクレオチドと接触させ、前記少なくとも1つのオリゴヌクレオチドが、配列番号2のヌクレオチド1〜2074および配列番号3のヌクレオチド1〜1237の中の5〜30個の連続するヌクレオチドを含むポリヌクレオチドの逆相補鎖に対して少なくとも50%の配列同一性を有することと、
それにより患者細胞または組織中の前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチド機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 患者細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、少なくとも1つの5〜30ヌクレオチド長のアンチセンスオリゴヌクレオチドと接触させ、前記少なくとも1つのオリゴヌクレオチドが、‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの天然アンチセンスの逆相補鎖に対して少なくとも50%の配列同一性を有することと、
それにより患者細胞または組織中の前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチド機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 患者細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、少なくとも1つの5〜30ヌクレオチド長のアンチセンスオリゴヌクレオチドと接触させ、前記少なくとも1つのオリゴヌクレオチドが、前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドに対するアンチセンスオリゴヌクレオチドに対して少なくとも50%の配列同一性を有することと、
それにより患者細胞または組織中の前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチド機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 患者細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの天然アンチセンスオリゴヌクレオチドの領域を標的とする少なくとも1つのアンチセンスオリゴヌクレオチドと接触させることと、
それにより患者細胞または組織中の前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチド機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 前記‘HSP70相互作用タンパク質C末端’(CHIP)の機能および/または発現が、対照に対してインビボまたはインビトロで増加する、請求項4に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの天然アンチセンス配列を標的とする、請求項4に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのコードおよび/または非コード核酸配列を含む核酸配列を標的とする、請求項4に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの重複および/または非重複配列を標的とする、請求項4に記載の方法。
- 前記少なくとも1つの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つの修飾された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合せから選択される1つ以上の修飾を含む、請求項4に記載の方法。
- 前記1つ以上の修飾が、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、二環式糖部分およびそれらの組合せから選択される1つ以上の修飾糖部分を含む、請求項9に記載の方法。
- 前記1つ以上の修飾が、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、カルバマート、炭酸エステル、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合せから選択される少なくとも1つの修飾されたヌクレオシド間結合を含む、請求項9に記載の方法。
- 前記1つ以上の修飾が、ペプチド核酸(PNA)、ロックト核酸(LNA)、アラビノ核酸(FANA)、類似体、誘導体およびそれらの組合せから選択される少なくとも1つの修飾ヌクレオチドを含む、請求項9に記載の方法。
- 前記少なくとも1つのオリゴヌクレオチドが、配列番号4〜11として記載されている少なくとも1つのオリゴヌクレオチド配列を含む、請求項1に記載の方法。
- 哺乳動物細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)遺伝子の機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、少なくとも1つの5〜30ヌクレオチド長の短鎖干渉RNA(siRNA)オリゴヌクレオチドと接触させ、前記少なくとも1つのsiRNAオリゴヌクレオチドが‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスポリヌクレオチドに特異的であり、前記少なくとも1つのsiRNAオリゴヌクレオチドが、前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子の少なくとも約5個の連続する核酸の相補的配列に対して少なくとも50%の配列同一性を有することと、
哺乳動物細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)の機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 前記オリゴヌクレオチドが、前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子と相補的な少なくとも約5個の連続する核酸の配列に対して少なくとも80%の配列同一性を有する、請求項14に記載の方法。
- 哺乳動物細胞または組織中の‘HSP70相互作用タンパク質C末端’(CHIP)の機能および/または発現をインビボまたはインビトロで調節する方法であって、
前記細胞または組織を、‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのセンスおよび/または天然アンチセンス鎖の非コードおよび/またはコード配列に特異的な約5〜30ヌクレオチド長の少なくとも1つのアンチセンスオリゴヌクレオチドと接触させ、前記少なくとも1つのアンチセンスオリゴヌクレオチドが、配列番号1〜3として記載されている少なくとも1つの核酸配列に対して少なくとも50%の配列同一性を有することと、
哺乳動物細胞または組織中の前記‘HSP70相互作用タンパク質C末端’(CHIP)の機能および/または発現をインビボまたはインビトロで調節することと
を含む方法。 - 少なくとも1つの修飾糖部分、少なくとも1つの修飾された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合せから選択される少なくとも1つの修飾を含む合成修飾オリゴヌクレオチドであって、前記オリゴヌクレオチドが、インビボまたはインビトロで‘HSP70相互作用タンパク質C末端’(CHIP)遺伝子とハイブリダイズし、正常対照と比べてその機能および/または発現を調節するアンチセンス化合物である、合成修飾オリゴヌクレオチド。
- 前記少なくとも1つの修飾が、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、カルバマート、炭酸エステル、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合せからなる群より選択されるヌクレオチド間結合を含む、請求項17に記載のオリゴヌクレオチド。
- 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17に記載のオリゴヌクレオチド。
- 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17に記載のオリゴヌクレオチド。
- ペプチド核酸、ロックト核酸(LNA)、類似体、誘導体およびそれらの組合せから選択される少なくとも1つの修飾ヌクレオチドを含む、請求項17に記載のオリゴヌクレオチド。
- 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、カルバマート、炭酸エステル、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合せからなる群より選択される修飾ヌクレオチドを含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。
- ペプチド核酸、ロックト核酸(LNA)、類似体、誘導体およびそれらの組合せから選択される修飾ヌクレオチドを含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。
- 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、二環式糖部分およびそれらの組合せから選択される少なくとも1つの修飾糖部分を含む、請求項17に記載のオリゴヌクレオチド。
- 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、二環式糖部分およびそれらの組合せから選択される修飾糖部分を含む複数の修飾を含む、請求項17に記載のオリゴヌクレオチド。
- 少なくとも約5〜30ヌクレオチド長であり、かつ‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスおよび/またはセンス鎖とハイブリダイズし、前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/また非コード核酸配列の少なくとも約5個の連続する核酸の相補配列に対して少なくとも約20%の配列同一性を有する、請求項17に記載のオリゴヌクレオチド。
- 前記‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/または非コード核酸配列の少なくとも約5個の連続する核酸の相補配列に対して少なくとも約80%の配列同一性を有する、請求項17に記載のオリゴヌクレオチド。
- インビボまたはインビトロで少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドとハイブリダイズし、正常対照と比べてその発現および/または機能を調節する、請求項17に記載のオリゴヌクレオチド。
- 配列番号4〜11として記載されている配列を含む、請求項17に記載のオリゴヌクレオチド。
- アンチセンス配列、相補的配列、対立遺伝子、相同体、アイソフォーム、バリアント、誘導体、変異体、フラグメントまたはそれらの組合せを含む1つ以上の‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドに特異的な1つ以上のオリゴヌクレオチドを含む組成物。
- 前記オリゴヌクレオチドが、配列番号4〜11として記載されているヌクレオチド配列のいずれか1つに対して少なくとも約40%の配列同一性を有する、請求項30に記載の組成物。
- 前記オリゴヌクレオチドが、配列番号4〜11として記載されているヌクレオチド配列を含む、請求項30に記載の組成物。
- 配列番号4〜11として記載されている前記オリゴヌクレオチドが、1つ以上の修飾または置換を含む、請求項32に記載の組成物。
- 前記1つ以上の修飾が、ホスホロチオアート、メチルホスホナート、ペプチド核酸、ロックト核酸(LNA)分子およびそれらの組合せから選択される、請求項33に記載の組成物。
- 少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドおよび/または少なくとも1つのそのコード産物に関連した疾患を予防または治療する方法であって、
前記少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドの天然アンチセンス配列と結合し、かつ前記少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドを調節する少なくとも1つのアンチセンスオリゴヌクレオチドの治療有効量を患者に投与することと、
それにより前記少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドおよび/または少なくとも1つのそのコード産物に関連した疾患を予防または治療することと
を含む方法。 - 前記少なくとも1つの‘HSP70相互作用タンパク質C末端’(CHIP)ポリヌクレオチドに関連した疾患が、CHIP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、神経炎症性疾患または障害、自己免疫疾患または障害、肥満症、糖尿病、アテローム性動脈硬化症、癌、AIDS、アテローム性動脈硬化プラーク、膠芽腫、アミロイド沈着に関連した疾患または障害、絨毛癌、星状細胞腫、アミロイドーシス、高脂血症、神経変性、腫瘍性形質転換、AIDS、転移、心筋梗塞、肺線維症、炎症、神経膠腫、血管疾患または障害、細胞損傷、非小細胞肺癌(NSCLC)、高コレステロール血症、脂肪肉腫、心血管疾患または障害、免疫不全、糸球体腎炎、静脈血栓症、病理過程、細胞ストレス、酸化ストレスに関連した疾患または障害、ポリグルタミン病、アグリソーム経路の機能障害に関連した疾患または障害、加齢に関連した疾患、障害または状態、ミスフォールドタンパク質の凝集に関連した疾患または障害、アルファ−シヌクレインのミスフォールディングおよび/または凝集に関連した疾患または障害、ならびにベータ−アミロイド(Abeta)代謝に関連した疾患または障害から選択される、請求項35に記載の方法。
- インビボ投与のための少なくとも1つのオリゴヌクレオチドを同定および選択する方法であって、
病的状態と関連する標的ポリヌクレオチドを選択することと、
前記選択された標的ポリヌクレオチドまたは前記選択されたポリヌクレオチドに対してアンチセンスであるポリヌクレオチドと相補的な少なくとも5個の連続するヌクレオチドを含む、少なくとも1つのオリゴヌクレオチドを同定することと、
アンチセンスオリゴヌクレオチドと、前記標的ポリヌクレオチドまたは前記選択されたポリヌクレオチドに対してアンチセンスであるポリヌクレオチドとのハイブリッドの熱融点を、ストリンジェントなハイブリダイゼーション条件下で測定することと、
得られた情報に基づいてインビボ投与のための少なくとも1つのオリゴヌクレオチドを選択することと
を含む方法。
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Also Published As
Publication number | Publication date |
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HK1219111A1 (zh) | 2017-03-24 |
EP2467482A4 (en) | 2013-12-11 |
CN102482670B (zh) | 2018-06-15 |
CA2771228C (en) | 2020-12-29 |
EP2467482A2 (en) | 2012-06-27 |
US20140288152A1 (en) | 2014-09-25 |
WO2011022606A2 (en) | 2011-02-24 |
US9725756B2 (en) | 2017-08-08 |
CN102482670A (zh) | 2012-05-30 |
US8791087B2 (en) | 2014-07-29 |
WO2011022606A3 (en) | 2011-08-11 |
KR20120051743A (ko) | 2012-05-22 |
KR101805213B1 (ko) | 2017-12-06 |
JP5943836B2 (ja) | 2016-07-05 |
EP2982755B1 (en) | 2020-10-07 |
EP2982755A1 (en) | 2016-02-10 |
CA2771228A1 (en) | 2011-02-24 |
US20120135941A1 (en) | 2012-05-31 |
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