JP5337337B2 - 血管形成のsiRNA阻害のための組成物及び方法 - Google Patents
血管形成のsiRNA阻害のための組成物及び方法 Download PDFInfo
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Description
本発明は、特異的に標的を定めて、VEGF、Flt−1及びFlk−1/KDR遺伝子からのmRNAの、RNAiに誘導される分解を引き起こすsiRNAに向けられている。この発明のsiRNA化合物及び組成物は、特に癌性腫瘍、加齢関連黄斑変性及び他の血管形成性疾患の治療のために、血管形成を阻止するために利用される。
図1A及び1Bは、siRNAで処理してない(「−」);非特異的siRNAで処理した(「非特異的」);又はヒトVEGFmRNAを標的とするsiRNAで処理した(「VEGF」)酸素欠乏293及びHela細胞におけるVEGF濃度(pg/ml)の棒グラフである。酸素欠乏でない293及びHela細胞におけるVEGF濃度(pg/ml)も示してある。各棒は、4つの実験の平均を表しており、誤差は、平均の標準偏差である。
図2は、siRNAで処理してない(「−」);非特異的siRNAで処理した(「非特異的」);又はヒトVEGFmRNAを標的とするsiRNAで処理した(「VEGF」)酸素欠乏NIH3T3細胞である。各棒は、6つの実験の平均を表しており、誤差は、平均の標準偏差である。
図3は、GFPsiRNA(濃い灰色の棒)又はヒトVEGFsiRNA(薄い灰色の棒)の存在下でヒトVEGFを発現するアデノウイルス(「AdVEGF」)を注入したマウスの網膜におけるヒトVEGF濃度(pg/全タンパク質)の棒グラフである。各棒は、5つの眼の平均を表し、誤差棒は、平均の標準誤差を表している。
図4は、GFPsiRNAの網膜下注入を受けた対照用眼(N=9;「GFPsiRNA」)、及びマウスVEGFsiRNAの網膜下注入を受けた眼(N=7;「マウスVEGFsiRNA」)においてレーザー誘導されたCNVの平均面積(mm2)を示す棒グラフである。誤差棒は、平均の標準誤差を表す。
図5は、pAAVsiRNA(この発明の組換えAAVウイルスベクターの生成に使用するシス作動性プラスミド)の図式表示である。「ITR」:AAV逆向き末端反復;「U6」:U6RNAプロモーター;「センス」:siRNAセンスコード配列;「アンチ」:siRNAアンチセンスコード配列;「ポリT」:ポリチミジン停止シグナル。
図6は、(A)網膜下又は(B)硝子体にマウス抗VEGFsiRNA(「mVEGF1.siRNA」)又は対照用siRNA(「GFP1.siRNA」)を注入したマウスの眼における処理おいてレーザー誘導されたCNVの平均面積(mm2)の棒グラフを示している。誤差棒は、平均の標準誤差を表している。(C)は、硝子体に、レーザー誘導後1日目に、siRNAを含まないリン酸緩衝塩溶液(「PBS」;レーザー誘導後14日目にCNV面積測定);レーザー誘導後14日目に、対照用siRNA(「GFP1.siRNA」;レーザー誘導後21日目にCNV面積測定);又はレーザー誘導後14日目に、マウス抗VEGFsiRNA(「mVEGF1.siRNA」;レーザー誘導後21日目にCNV面積測定)を注入されたマウスの眼においてレーザー誘導されたCNVの平均面積(mm2)の棒グラフである。誤差棒は、平均の標準誤差を表している。
図7は、ヒト抗VEGFsiRNA(「Cand5」)及び対照用siRNA(「GFP1.siRNA」)を、注入後0(n=2;プレ−siRNA注入)、6(n=3)、10(n=3)及び14(n=3)日目で網膜下に注入されたマウスの眼におけるVEGFタンパク質のパーセント(「VEGF%」)のグラフである。VEGF%=(Cand5眼中の[VEGF]/GFP1.siRNA眼中の[VEGF])*100。
別途示さない限り、本明細書中では、すべての核酸配列を、5’から3’への向きで与える。又、すべての核酸配列中のデオキシリボヌクレオチドは、大文字で表され(例えば、デオキシチミジンは、「T」である)、核酸配列中のリボヌクレオチドは、小文字で表される(例えば、ウリジンは、「u」である)。
siRNAのデザイン − ヒトのVEGFmRNAの5’末端から329ntに位置する19ntの配列:AAACCTCACCAAGGCCAGCAC (SEQ ID NO:51)を標的配列として選択した。それが、如何なる他の遺伝子に由来するmRNAにも含まれないことを確実にするために、この標的配列を、NCBIにより提供されたBLASTサーチエンジンにエンターさせた。BLASTアルゴリズムの利用は、Altschul等(1990), J.Mol.Biol.215:403-410及びAltschul等(1997), Nucleic Acids Res.25:3389-3402(これらの開示を、参考として、本明細書中にそっくりそのまま援用する)に記載されている。この標的配列を含む他のmRNAは見出されなかったので、siRNA二本鎖を、この配列を標的とするように合成した(Dharmacon Research, Inc., CO, Lafayette)。
センス:
実施例1で概説した実験を、ヒト293、HeLa及びARPE19細胞で、濃度10〜50nMの範囲のsiRNAを利用して反復した。Cand5 siRNAの、VEGF生成をダウンレギュレートする能力は、約13nM siRNAまで穏やかに増大したが、これより高濃度では平坦効果が見られた。これらの結果は、平坦効果が、このsiRNAをトランスフェクトされなかった少数の細胞からのVEGF生成を反映しているようなので、mRNAのsiRNA媒介のRNAi分解の触媒的性質を強調している。このsiRNAをトランスフェクトされた細胞の大部分について、低酸素状態により誘導された増大したVEGFmRNA生成は、約13nMより高いsiRNA濃度において、標的mRNAのsiRNA誘導された分解により追い越される。
NIH3T3マウス繊維芽細胞を、24ウェルプレート中で、標準的条件下で、これらの細胞が、トランスフェクションの1日前に約50%集密になるように生育させた。ヒトVEGF siRNA Cand5を、NIH3T3マウス繊維芽細胞に実施例1におけるようにトランスフェクトした。次いで、低酸素状態を、トランスフェクトされた細胞において誘導して、マウスVEGF濃度を、ELISAによって、実施例1におけるように測定した。
VEGFは、加齢関連黄斑変性(ARMD)のヒト患者の網膜色素上皮(RPE)細胞においてアップレギュレートされる。機能的siRNAが、RPE細胞にイン・ビボで送達されうることを示すために、GFPを、マウスの網膜で組換えウイルスを用いて発現させ、GFP発現をsiRNAを用いて抑制した(silenced)。
siRNAが、イン・ビボで機能化されたVEGFを標的とすることを示すために、外因性のヒトVEGF発現カセットを、実施例4におけるように、網膜下注射により、アデノウイルスによってマウスRPE細胞に送達した。一方の眼は、Cand5 siRNAを受け、反対側性の眼は、GFP mRNAを標的とするsiRNAを受けた。これらの動物を、注射の60時間後に犠牲にして、それらの注射された眼を取り出して、摘出後、液体N2中で急速冷凍した。次いで、それらの眼を、溶解用緩衝液中でホモジェナイズして、総タンパク質を、標準的なBradfordタンパク質アッセイ(Roche, ドイツ国)を利用して測定した。これらの試料を、ヒトVEGFを実施例1に記載したようにELISAによってアッセイする前に、総タンパク質につき標準化した。
ARMDにおける脈絡膜新血管新生は、RPE細胞におけるVEGFのアップレギュレーションのためであるという証拠がある。このヒトの病状は、レーザーを利用して網膜上の一点を焼くこと(「レーザー光凝固」又は「レーザー誘導」)により、マウスにおいてモデル化することができる。治癒過程に際して、VEGFは、焼かれた領域のRPE細胞においてアップレギュレートされ、これが、脈絡膜の血管再生へと導くと考えられる。このモデルは、マウス脈絡膜新血管新生(「CNV」)モデルと呼ばれる。
この発明のsiRNAの送達のための組換えAAVベクターの生成のための「シス作用性」プラスミドを、本質的にSamulski R等(1987), 前出に記載されたようにして、PCRベースのサブクローニングにより生成した。このシス作用性プラスミドは、「pAAV siRNA」と呼ばれる。
マウスのVEGFに向けられたsiRNAの、実験的レーザー誘導性脈絡膜新血管新生(CNV)をマウスにおいて阻止する能力を、下記のように試験した。
Cand5siRNAの、イン・ビボで経時的にVEGFのRNAiを誘導する能力を下記のように評価した。
10匹の自然のままのカニクイザル(Macaca fascicularis)が、両眼の網膜のレーザー光凝固にかけられ、脈絡膜新血管新生(「CNV」)が誘導されることが予想される。下記は、Cand5siRNAの、サルにおけるCNVの面積を減少させる能力を評価するために意図された実験計画を表す。Cand5により標的とされたVEGF RNA配列は、ヒトと M. fascicularisの両方において同じであり、Cand5は、M. fascicularisのVEGF RNAのRNAiを誘導することが予想される。
Claims (65)
- センスRNA鎖及びアンチセンスRNA鎖を含む単離されたsiRNAであって、該センス及びアンチセンス鎖がRNA二本鎖を形成し、且つ該センス鎖が、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の隣接する19〜25ヌクレオチド標的配列と同じヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含む、当該単離されたsiRNA。
- ヒトVEGFmRNAを、VEGF121mRNA(SEQ ID NO:2);VEGF165mRNA(SEQ ID NO:3);VEGF189mRNA(SEQ ID NO:4)及びVEGF206mRNA(SEQ ID NO:5)よりなる群から選択する、請求項1に記載のsiRNA。
- センスRNA鎖が、一つのRNA分子を含み、且つアンチセンスRNA鎖が、一つのRNA分子を含む、請求項1に記載のsiRNA。
- RNA二本鎖を形成するセンス及びアンチセンスRNA鎖が、単一鎖のヘアピンにより共有結合されている、請求項1に記載のsiRNA。
- siRNAが、非ヌクレオチド物質を更に含む、請求項1に記載のsiRNA。
- センス及びアンチセンスRNA鎖が、ヌクレアーゼ分解に対して安定化されている、請求項1に記載のsiRNA。
- センスRNA鎖が、第一の3’オーバーハングを含み且つアンチセンスRNA鎖が、第二の3’オーバーハングを含む、請求項3に記載のsiRNA。
- 第一の3’オーバーハングが、2ヌクレオチドを含み且つ第二の3’オーバーハングが、2ヌクレオチドを含む、請求項7に記載のsiRNA。
- 第一及び第二の3’オーバーハングを構成する2ヌクレオチドが、ジチミジル酸(TT)又はジウリジル酸(uu)である、請求項8に記載のsiRNA。
- 請求項1に記載のsiRNAを含む網膜色素上皮細胞。
- センスRNA鎖及びアンチセンスRNA鎖を含むsiRNAを発現するための核酸配列を含む組換えプラスミドであって、該センス及びアンチセンスRNA鎖が、RNA二本鎖を形成し、且つセンスRNA鎖が、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の隣接する19〜25ヌクレオチドの標的配列と同じヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含む、当該組換えプラスミド。
- siRNAを発現するための核酸配列が、誘導性又は調節可能なプロモーターを含む、請求項11に記載の組換えプラスミド。
- siRNAを発現するための核酸配列が、ポリT停止配列に操作可能に結合されたセンスRNA鎖をコードする配列をヒトU6RNAプロモーターの制御下に含み、ポリT停止配列に操作可能に結合されたアンチセンスRNA鎖をコードする配列をヒトU6RNAプロモーターの制御下に含む、請求項11に記載の組換えプラスミド。
- プラスミドが、pAAVsiRNAである、請求項13に記載の組換えプラスミド。
- センスRNA鎖とアンチセンスRNA鎖を含むsiRNAの発現のための核酸配列を含む組換えウイルスベクターであって、該センス及びアンチセンスRNA鎖は、RNA二本鎖を形成し、センスRNA鎖は、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の隣接する19〜25ヌクレオチドの標的配列と同じヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含む、上記の組換えウイルスベクター。
- siRNAの発現のための核酸配列が、誘導性又は調節可能なプロモーターを含む、請求項15に記載の組換えウイルスベクター。
- siRNAの発現のための核酸配列が、ポリT停止配列に操作可能に結合されたセンスRNA鎖をコードする配列をヒトU6RNAプロモーターの制御下に含み、ポリT停止配列に操作可能に結合されたアンチセンスRNA鎖をコードする配列をヒトU6RNAプロモーターの制御下に含む、請求項15に記載の組換えウイルスベクター。
- 組換えウイルスベクターを、アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、レトロウイルスベクター、及びヘルペスウイルスベクターよりなる群から選択する、請求項15に記載の組換えウイルスベクター。
- 組換えウイルスベクターが、水疱性口内炎ウイルス、狂犬病ウイルス、エボラウイルス、又はモコラウイルスからの表面タンパク質によりシュードタイプ分けすることができる、請求項15に記載の組換えウイルスベクター。
- 組換えウイルスベクターが、アデノ随伴ウイルスベクターを含む、請求項18に記載の組換えウイルスベクター。
- siRNA及び製薬上許容しうるキャリアーを含む医薬組成物であって、該siRNAが、センスRNA鎖及びアンチセンスRNA鎖を含み、該センス及びアンチセンスRNA鎖はRNA二本鎖を形成し、そしてセンスRNA鎖が、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の隣接する19〜25ヌクレオチドの標的配列と同じヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含む、上記の医薬組成物。
- リポフェクチン、リポフェクタミン、セルフェクチン、ポリカチオン又はリポソームを更に含む、請求項21に記載の医薬組成物。
- 請求項11に記載のプラスミド又は生理的に許容されるその塩、及び製薬上許容しうるキャリアーを含む医薬組成物。
- リポフェクチン、リポフェクタミン、セルフェクチン、ポリカチオン又はリポソームを更に含む、請求項23に記載の医薬組成物。
- 請求項15に記載のウイルスベクター及び製薬上許容しうるキャリアーを含む医薬組成物。
- 患者に投与して、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体の発現を阻止するために用いられる組成物であって、該組成物は、センスRNA鎖及びアンチセンスRNA鎖を含む有効量のsiRNAを含み、該センスRNA鎖とアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の隣接する19〜25ヌクレオチドの標的配列と同じヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含み、それでヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体を分解することを特徴とする当該組成物。
- 患者が、ヒトである、請求項26に記載の組成物。
- ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体の発現が、患者の一方又は両方の眼において阻止される、請求項26に記載の組成物。
- ヒトVEGFmRNA又はこれらの選択的スプライス型若しくは変異体の発現が、患者の網膜色素上皮細胞において阻止される、請求項26に記載の組成物。
- siRNAの有効量が、1〜100nMである、請求項26に記載の組成物。
- siRNAを、送達用試薬と共に投与する、請求項26に記載の組成物。
- 送達用薬剤を、リポフェクチン、リポフェクタミン、セルフェクチン、ポリカチオン及びリポソームよりなる群から選択する、請求項31に記載の組成物。
- 送達用薬剤が、リポソームである、請求項32に記載の組成物。
- リポソームが、該リポソームを血管形成部位又はその近くの細胞を標的とさせるリガンドを含む、請求項33に記載の組成物。
- リガンドが、腫瘍細胞又は血管内皮細胞上のレセプターに結合する、請求項34に記載の組成物。
- リガンドが、モノクローナル抗体を含む、請求項35に記載の組成物。
- リポソームが、オプソニン作用阻害成分で改変されている、請求項33に記載の組成物。
- オプソニン作用阻害成分が、PEG、PPG又はこれらの誘導体を含む、請求項37に記載の組成物。
- siRNAが、組換えプラスミドから発現される、請求項26に記載の組成物。
- siRNAが、組換えウイルスベクターから発現される、請求項26に記載の組成物。
- 組換えウイルスベクターが、アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、レトロウイルスベクター又はヘルペスウイルスベクターを含む、請求項40に記載の組成物。
- 組換えウイルスベクターが、水疱性口内炎ウイルス、狂犬病ウイルス、エボラウイルス、又はモコラウイルスからの表面タンパク質によりシュードタイプ分けすることができる、請求項41に記載の組成物。
- 組換えウイルスベクターが、アデノ随伴ウイルスベクターを含む、請求項40に記載の組成物。
- siRNAを、新血管新生の治療のために非経口投与経路により投与する、請求項26に記載の組成物。
- 非経口投与経路を、血管内投与、組織周辺及び組織内投与、皮下注射又はデポジション、皮下点滴、眼内投与、及び新血管新生部位又はその近くへの直接適用よりなる群から選択する、請求項44に記載の組成物。
- 血管内投与を、静脈内ボーラス注射、静脈内点滴、動脈内ボーラス注射、動脈内点滴及び血管系へのカテーテル点滴注入法よりなる群から選択する、請求項45に記載の組成物。
- 組織周辺及び組織内注射が、腫瘍周辺への注射又は腫瘍内部への注射を含む、請求項45に記載の組成物。
- 眼内投与が、硝子体内、網膜内、網膜下、テント下、眼窩周囲及び眼窩後、経角膜又は経強膜投与を含む、請求項45に記載の組成物。
- 新血管新生部位又はその近くへの直接適用が、カテーテル、角膜ペレット、眼滴瓶、坐薬、多孔性物質を含むインプラント、非多孔性物質を含むインプラント、又はゼラチン状物質を含むインプラントによる適用、を含む、請求項45に記載の組成物。
- 新血管新生部位が、眼内にあり、新血管新生部位又はその近くへの直接適用が、眼内インプラントによる適用を含む、請求項45に記載の組成物。
- 眼内インプラントが、生物分解性である、請求項50に記載の組成物。
- 患者における血管形成を阻止するために用いられる組成物であって、該組成物は、センスRNA鎖及びアンチセンスRNA鎖を含むsiRNAの有効量を含み、該センス及びアンチセンスRNA鎖は、RNA二本鎖を形成し、該センスRNA鎖は、ヒトのVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の19〜25の隣接ヌクレオチドの標的配列と同一のヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含む当該組成物。
- 血管形成が、病原性である、請求項52に記載の組成物。
- 血管形成を、患者の一方又は両方の眼において阻止する、請求項52に記載の組成物。
- 血管形成を、患者の網膜色素上皮細胞において阻止する、請求項52に記載の組成物。
- 患者における血管形成性疾患を治療するために用いられる組成物であって、該組成物は、センスRNA鎖及びアンチセンスRNA鎖を含む有効量のsiRNAを含み、該センス及びアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトのVEGFmRNA又はこれらの選択的スプライス型若しくは変異体中の19〜25の隣接ヌクレオチドの標的配列と同一のヌクレオチド配列を含み、該センスRNA鎖が、SEQ ID NO:77の配列を含み、且つ該アンチセンスRNA鎖が、SEQ ID NO:78の配列を含み、それで、血管形成性疾患と関連する血管形成が阻止される当該組成物。
- 血管形成性疾患が、癌と関連する腫瘍を含む、請求項56に記載の組成物。
- 癌を、乳癌、肺癌、頭頚部癌、脳癌、腹部癌、大腸癌、結腸直腸癌、食道癌、胃腸癌、神経膠腫、肝臓癌、舌癌、神経芽細胞腫、骨肉腫、卵巣癌、膵臓癌、前立腺癌、網膜芽細胞腫、ウィルムス腫瘍、多発性骨髄腫、皮膚癌、リンパ腫及び血液癌よりなる群から選択する、請求項57に記載の組成物。
- 血管形成性疾患を、糖尿病性網膜症、及び加齢関連黄斑変性よりなる群から選択する、請求項56に記載の組成物。
- 血管形成性疾患が、加齢関連黄斑変性である、請求項59に記載の組成物。
- siRNAを、血管形成性疾患を治療するための医薬と共に投与し、該医薬が、siRNAとは異なる、請求項56に記載の組成物。
- 血管形成性疾患が癌であり、医薬が化学療法剤を含む、請求項61に記載の組成物。
- 化学療法剤を、シスプラチン、カルボプラチン、シクロホスファミド、5−フルオロウラシル、アドリアマイシン、ダウノルビシン及びタモキシフェンよりなる群から選択する、請求項61に記載の組成物。
- siRNAを、血管形成性疾患の治療のためにデザインされた他の治療法と組み合せて患者に投与する、請求項56に記載の組成物。
- 血管形成性疾患が癌であり、siRNAを、放射線療法、化学療法又は外科手術と組み合せて投与する、請求項64に記載の組成物。
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