JP5066095B2 - 染色体dnaに標的化されるオリゴマーによる遺伝子発現の調節 - Google Patents
染色体dnaに標的化されるオリゴマーによる遺伝子発現の調節 Download PDFInfo
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Description
関連出願の相互参照:本願は、2005年11月17日に出願された米国仮出願第60/738,103号の優先権を主張する。
本研究は、国立衛生研究所によって授与された補助金(NIGMS60642及び73042;並びにP50CA70907)の下、連邦政府の支援を受けて為された。連邦政府は、本発明に対して一定の権利を有する。
細胞性取り込みを促進するために、ペネトラチン、トランスポータン、Tatペプチド、核移行シグナル(NLS)及びその他のペプチドなどのペプチドをオリゴマーに付着させることが可能である(例えば、Nielsen, 2004;Kaihatsu et al, 2003;Kaihatsu, et al, 2004;及び参考文献7を参照されたい。)。あるいは、リゾレシチンなどの透過剤を用いて細胞を透過化した後、オリゴマーと接触させることができる。インビトロでオリゴマーを細胞に送達させるために、ウイルス形質導入を使用することが可能である(例えば、レンチウイルス形質導入、例えば、参考文献7を参照されたい。)。しかしながら、本発明のある種の実施形態において、接触工程はウイルス形質導入を含まないことが好ましい。さらなる好ましい実施形態において、接触工程はウイルス形質導入を含まず、及びオリゴマーは、核移行ペプチドに付着されない。
MVP:以前に記載した方法(Janowski et al., 2005)を用いて、転写開始部位に対して−82から−64(−82/−64)に位置する主要ヴォールトタンパク質(MVP;Lange et al, 2000)及びp53部位(−54/−36)を標的とするdsRNAは、それぞれ、RNA及びタンパク質のレベルで、2.9倍及び3.8倍のMVP発現の増加を引き起こした。
ヒトVEGF遺伝子のプロモーター領域は、性質が決定されている(例えば、Tischer et al, 1991を参照されたい。)。転写開始部位は、公開されている配列(GenBank受付番号AF095785.1)中の2363位に位置する。テンプレート鎖に対して完全に相補的であり、及び遺伝子の転写開始部位付近(−50から+25、転写開始は+1である。)を標的とする19マーのagRNAを調製する。典型的なagRNAは、表4に示されている(第二の鎖及び二ヌクレオチド突出部は示されていない。)。
遺伝子活性化は、遺伝子発現の低い基底レベルに対してさらに容易に観察できると、本発明者らは推論した。従って、本発明者らの仮説に取り組むために、本発明者らは、T47D細胞中で観察されるより、ずっと低いPRタンパク質発現の基底レベルを有する乳癌細胞株であるMCF−7細胞中に二重鎖RNAを導入した(Janowski et al(2006a) Nature Struc.Mol.Biol 13:787−792; Jenster et al(1997) Proc Natl Acad Sci USA 94:7879−7884)。
PR10又はPR12を最初に細胞に添加した場合には、本発明者らは、その後のPR11の添加が活性化をもたらさないことを観察した。最初にPR11が細胞に添加された場合には、PR10又はPR12は、遺伝子活性化を遮断しなかった。これらの競合アッセイは、非活性なRNAPR10及びPR12がPR11と同一の標的配列に結合することを示している。認識は、PR11の結合を遮断し、PR発現の活性化を妨げるのに十分である。PR10及びPR12とのPR11の競合は、PRのRNA媒介性活性化の標的及び配列特異性をさらに実証する。
Claims (14)
- インビトロで培養された哺乳動物細胞中のp53遺伝子の標的転写物の合成を選択的に増加させる方法であり、前記方法は、
前記p53遺伝子の標的プロモーター内の領域に相補的な配列番号7〜9からなる群より選択される配列を1つの鎖として有する二本鎖RNAポリヌクレオチドオリゴマーを前記細胞に導入して、前記標的転写物の合成を選択的に増加させる工程、及び
前記標的遺伝子の生じた選択的な増加された合成を検出する工程、を含み、前記領域が前記p53遺伝子の転写開始部位に対して−13から+12ヌクレオチドの間に位置している、前記方法。 - 領域が、p53遺伝子の転写開始部位を含む請求項1に記載の方法。
- 標的プロモーターが、標的転写物のイソフォームのプロモーターである請求項1に記載の方法。
- 標的プロモーターが、標的転写物の予め定められたイソフォームのプロモーターであり、及び前記イソフォームの合成が阻害される請求項1に記載の方法。
- 前記ポリヌクレオチドオリゴマーが2’化学修飾を有するヌクレオチドを含む請求項1に記載の方法。
- 前記ポリヌクレオチドオリゴマーが、ホスホロチオアートヌクレオチド間連結、2’−O−メチルリボヌクレオチド、2’−デオキシ−2’−フルオロリボヌクレオチド、2’−デオキシリボヌクレオチド、ユニバーサル塩基ヌクレオチド、5−C−メチルヌクレオチド、逆位デオキシ脱塩基残基の取り込み及びロックされた核酸からなる群から選択される血清安定性増強化学修飾を含む請求項1に記載の方法。
- 導入工程がウイルス形質導入を含まない請求項1に記載の方法。
- 導入工程がウイルス形質導入を含まず、及び細胞が前記ポリヌクレオチドオリゴマーから実質的になる組成物と接触される請求項1に記載の方法。
- 導入工程がウイルス形質導入を含まず、及び標的転写物の少なくとも2倍の増加された合成が生じる請求項1に記載の方法。
- 標的プロモーターの単一の領域が標的化され、及び標的転写物の少なくとも2倍の増加された合成が生じる請求項1に記載の方法。
- 前記ポリヌクレオチドオリゴマーの1から100nM濃度を用いて細胞に導入する請求項1に記載の方法。
- 細胞が癌細胞である請求項1に記載の方法。
- 哺乳動物細胞中のp53遺伝子の標的転写物の合成を選択的に増加させるための、前記p53遺伝子の標的プロモーター内の転写開始部位に対して−13から+12ヌクレオチドの間に位置している領域に相補的な配列番号7〜9からなる群より選択される配列を1つの鎖として有する単離された又は合成の二本鎖RNAポリヌクレオチドオリゴマー。
- 前記ポリヌクレオチドオリゴマーが請求項2〜6のいずれか1項に定義されるポリヌクレオチドオリゴマーである請求項13に記載のポリヌクレオチドオリゴマー。
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US7709456B2 (en) | 2010-05-04 |
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