JP6629712B2 - 細胞内貫通能を持ってrna干渉を誘導する核酸分子およびその用途 - Google Patents
細胞内貫通能を持ってrna干渉を誘導する核酸分子およびその用途 Download PDFInfo
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- JP6629712B2 JP6629712B2 JP2016250474A JP2016250474A JP6629712B2 JP 6629712 B2 JP6629712 B2 JP 6629712B2 JP 2016250474 A JP2016250474 A JP 2016250474A JP 2016250474 A JP2016250474 A JP 2016250474A JP 6629712 B2 JP6629712 B2 JP 6629712B2
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Description
さらに本発明は、結合組織成長因子(CTGF)をコードするmRNAと相補的な領域を含む第1鎖と、前記第1鎖と相補的結合を形成する第2鎖で構成されるRNAi誘導用二本鎖核酸分子において、前記核酸分子に含まれている1〜31個のヌクレオチドのホスフェートバックボーンがホスホロチオエートまたは、ホスホロジチオエートで置換されていて、親油性化合物が結合されていて、前記RNAiを誘導する二本鎖の核酸分子は、配列番号149および150の塩基対、配列番号151および152の塩基対、および配列番号153および154の塩基対で構成された群から選択された塩基対を持つことを特徴とする、細胞内貫通能を持つCTGF発現抑制用核酸分子を提供する。
第1鎖は、目的核酸と相補的な一部領域を含み、この時、目的核酸と相補的な一部領域を含む領域の長さは16〜31nt、19〜31nt、または、19〜21ntであることを特徴とする。なお、第2鎖は、13〜25nt、13〜21nt、または、16〜21ntの長さを持つことを特徴とする。
効果的な自己伝達(self delivery)構造のための種々の化学的改変の導入に先立ち、CTGFを標的にする高効率のRNAiを誘導する二本鎖の核酸分子を確保するために、CTGFに対する50種の標的配列をデザインした後、スクリーニング(screening)を進行した。
GAPDH−reverse 5’−GAC AAG CTT CCC GTT CTC AG−3’(配列番号146)
CTGF−forward 5’−CAA GGG CCT CTT CTG TGA CT−3’(配列番号147)
CTGF−reverse 5’−ACG TGC ACT GGT ACT TGC AG−3’(配列番号148)
2−1:コレステロール改変に係る影響
先に、コレステロール改変が、lasiRNAの伝達に及ぼす影響を調べるために、lasiRNAセンス鎖、すなわち第2鎖の5’末端をcy3で標識した後、コレステロール有無に係る取り込み差を蛍光顕微鏡で確認した。すなわち、HeLa細胞にcy3で標識したlasiRNAまたはchol−lasiRNA構造体を1μMでインキュベートした後、3時間後に蛍光顕微鏡で観察して細胞内に伝達された程度を比較した。
追加的に、ホスホロチオエートを直接siRNAに導入する改変を行う場合、lasiRNAの取り込み効率を増加させるのか確認するために、コレステロールを結合させたchol−lasiRNAのアンチセンス鎖、すなわち第1鎖の3’オーバーハングにPS改変を導入して、PS改変に係るchol−lasiRNAの取り込み効率変化をテストした。HeLa細胞にcy3で標識したchol−lasiRNA−PS(N)構造体を1μMでインキュベートした後、3時間後に蛍光顕微鏡で観察して細胞内に伝達された程度を比較した。構造体の間の細胞貫通能の正確な比較のために、chol−lasiRNA−PS0が最小限の蛍光を見せる条件をセット後、他の構造体の蛍光強度を比較した。
実施例2でCy3−標識化lasiRNAを利用した内部化(internalization)実験の結果、lasiRNA構造にコレステロールとPS改変を直接導入して伝達ビヒクルや追加的な試薬がなくともlasiRNAの効果的な細胞内伝達が可能であることが確認された。しかし、siRNAに種々の化学的改変を導入する場合、siRNAの活性を多少減少させたり、改変によりsiRNAの活性が急激に減少すると知られているが、各改変がlasiRNAの活性に及ぼす影響を調べるために、多様な構造のlasiRNAをHeLa細胞にトランスフェクションした後、CTGF mRNAの発現変化を測定して、各改変がlasiRNAの遺伝子発現抑制に及ぼす影響を測定した。
コレステロール以外に他の親油性化合物改変(lipophilic modification)(すなわち、疎水性化合物改変(hydrophobic modification))を用いる場合の影響を調べるために、次の配列でサバイビン(survivin)を目的遺伝子にした本発明に係るcp−lasiRNA(cell penetrating lasiRNA)を製造した。この時、cp−lasiRNA−1はコレステロールが結合されたもので、cp−lasiRNA−2はコレステロールの代わりに該当位置にトコフェノールを結合したもので、cp−lasiRNA−3はコレステロールの代わりにセンス鎖の5’位置にステアリン酸を結合したものである。
cp−lasiRNA(survivin)Antisense 31nt:5’UGAAAAUGUUGAUCUCCUUUCCUAAGA*C*A*T*T 3’(配列番号169)
cp−lasiRNA(survivin)Sense:5’GAGAUCAACAUUUU*C*A*cholesterol.3’(配列番号170)
下線:OMe改変、*:PS(ホスホロチオエート結合)
Forward 5’−GCA CCA CTT CCA GGG TTT AT−3’(配列番号172)
Reverse 5’−CTC TGG TGC CAC TTT CAA GA−3’(配列番号173)
本発明に係る核酸分子の第1鎖の長さに係る標的遺伝子抑制効率を調べるために、同じ16ntの第2鎖(センス鎖)に31ntアンチセンスまたは21ntのアンチセンスを組み合わせてcp−lasiRNAを作った後A549細胞株に処理した。
cp−lasiRNA(survivin)Antisense 31nt:5’UGAAAAUGUUGAUCUCCUUUCCUAAGA*C*A*T*T3’(配列番号169)
cp−lasiRNA(survivin)Sense:5’GAGAUCAACAUUUU*C*A*cholesterol.3’(配列番号170)
<cp−lasiRNA(survivin)21mer>
cp−lasiRNA(survivin)Antisense 21nt:5’UGAAAAUGUUGAUCUCCU*U*U*C*C3’(配列番号171)
cp−lasiRNA(survivin)Sense:5’GAGAUCAACAUUUU*C*A*cholesterol.3’(配列番号170)
下線:OMe改変、*:PS(ホスホロチオエート結合)
<cp−lasiRNA(CTGF)31mer>
cp−lasiRNA(CTGF)Antisense 31nt:5’UCUUCCAGUCGGUAAGCCGCGAGGGCA*G*G*C*C3’(配列番号174)
cp−lasiRNA(CTGF)Sense:5’CTTACCGACTGGAA*G*A*chol.3’(配列番号175)
<cp−lasiRNA(CTGF)21mer>
cp−lasiRNA(CTGF)Antisense 21nt:5’UCUUCCAGUCGGUAAGC*C*G*C*G 3’(配列番号176)
cp−lasiRNA(CTGF)Sense:5’CTTACCGACTGGAA*G*A*chol.3’(配列番号175)
下線:OMe改変、*:PS(ホスホロチオエート結合)
図9に示したように、CTGFを標的とするcp−lasiRNAの場合、トランスフェクションとインキュベート共に31ntアンチセンスを持つ場合が21ntアンチセンスを持つ場合よりさらに高い標的遺伝子抑制効率を示し(図9A−B)、サバイビンを標的とするcp−lasiRNAをインキュベートした場合にも同様に31ntアンチセンスの標的遺伝子抑制効率が高く観察されることを確認した。すなわち、本発明に係る核酸分子は、19nt〜31ntの様々な長さのアンチセンス、すなわち第1鎖を持つ核酸分子のデザインが可能で、これを利用して効果的に標的遺伝子抑制が可能であるが、31ntの長さを持つ場合が21ntのアンチセンスより効率的に標的遺伝子抑制が可能であることが確認された。
核酸分子中一つ以上のヌクレオチドホスフェートバックボーンをホスホロチオエートに改変させたこと以外に図10のような構造のホスホロジチオエート(PS2)に改変する場合、効果を下記の通り調べた。
cp−lasiRNA(survivin)Antisense 31nt:5’UGAAAAUGUUGAUCUCCUUUCCUAAGA*C*A*T*T3’(配列番号169)
cp−lasiRNA(survivin)Sense:5’GAGAUCAACAUUUU*C*A*cholesterol.3’(配列番号170)
下線:OMe改変、*:PS(ホスホロチオエート結合又はホスホロジチオエート結合)
現在RNAi技術を利用した治療剤開発で最も困難なことの一つは、インビボでの効果的なRNA伝達技術の開発である。現在開発されている多くの伝達体技術をこのインビトロ上では、高い効率を持つ反面、インビボに適用された場合、その効率が顕著に減少する問題点を有している。これに対して、本発明に係る核酸分子がインビボでも高い遺伝子抑制効果を持つのか確認するために、別途の伝達体を用いることなくcp−lasiRNAだけをラットの皮膚に注射して標的遺伝子の発現抑制効果を比較した。
cp−lasiRNA(CTGF)Sense Rat:5’−CCTACCGACTGGAA*G*A*choleterol.3’(配列番号178)
下線:OMe改変、*:PS(ホスホロチオエート結合)
siRNAとしては下記を利用した。
siRNA(CTGF)antisense:5’−CUGCCUACCGACUGGAAGATT−3’(配列番号179)
siRNA(CTGF)sense:5’−CUGCCUACCGACUGGAAGATT−3’(配列番号180)
下線:OMe改変
Forward 5’−GGC TCG CAT CAT AGT TG−3’(配列番号181)
Reverse 5’−CGG GAA ATG CTG TGA GGA GT−3’(配列番号182)
Claims (8)
- 標的核酸と100%相補的であり、そしてホスホロチオエート結合の少なくとも1つ及び2’位置においてO−メチル基で改変されたヌクレオチドの少なくとも1つを含む、31ntの長さの第1鎖と、
前記第1鎖と相補的に結合し、ホスホロチオエート結合の少なくとも1つ及び2’位置においてO−メチル基で改変されたヌクレオチドの少なくとも1つを含み、そしてその3’末端に結合したコレステロール部分をさらに含む、16ntの長さの第2鎖と、
を含む長い非対称形RNAi誘導用二本鎖核酸(lasiRNA)であって、前記第1鎖の核酸は4〜17のホスホロチオエート結合を有し、前記第1鎖が、前記第2鎖が結合する二本鎖領域及び前記第2鎖が結合しない一本鎖領域を有するように、前記第2鎖が、前記第1鎖に結合し、そして前記第1鎖の5’末端及び前記第2鎖の3’末端が、平滑末端を形成し、そして前記第1鎖のホスホロチオエート結合がその一本鎖領域に位置する、前記長い非対称形RNAi誘導用二本鎖核酸(lasiRNA)。 - 前記第1鎖が、4個のホスホロチオエート結合を含む、請求項1に記載の核酸。
- 前記第2鎖が、1〜3個のホスホロチオエート結合を含む、請求項1に記載の核酸。
- 前記標的核酸は、mRNA、microRNA、piRNA、コードDNA配列及び非コードDNA配列中いずれか一つであることを特徴とする請求項1に記載の核酸。
- 前記第1鎖で前記一本鎖領域を構成するヌクレオチド中少なくとも一つ以上がフェニル基を持つデオキシアデノシン誘導体を含むことを特徴とする請求項1に記載のRNAi誘導用核酸。
- 請求項1〜5のいずれか一項に記載の核酸を含む遺伝子発現抑制用組成物。
- 請求項1〜5のいずれか一項に記載の前記核酸を細胞内に導入させる工程を含む、インビトロの細胞内の目的遺伝子の発現抑制方法。
- 請求項1〜5のいずれか一項に記載の核酸を含み、目的遺伝子が標的核酸を含む、目的遺伝子の発現抑制用医薬組成物。
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EP2853597B1 (en) | 2018-12-26 |
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HK1211319A1 (en) | 2016-05-20 |
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JP6139671B2 (ja) | 2017-05-31 |
KR101581655B9 (ko) | 2015-12-31 |
KR101567576B1 (ko) | 2015-11-10 |
CN104755620B (zh) | 2018-03-02 |
US10125362B2 (en) | 2018-11-13 |
JP2015518721A (ja) | 2015-07-06 |
US20210207137A1 (en) | 2021-07-08 |
JP6999590B2 (ja) | 2022-01-18 |
JP2017093448A (ja) | 2017-06-01 |
EP2853597A4 (en) | 2016-01-27 |
US10883105B2 (en) | 2021-01-05 |
CN108148838A (zh) | 2018-06-12 |
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