JP5449639B2 - HIF−1アルファのsiRNA阻害に関する組成物及び方法 - Google Patents
HIF−1アルファのsiRNA阻害に関する組成物及び方法 Download PDFInfo
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Description
本願は、2002年11月1日に出願された米国仮出願第60/423,262号明細書の利益を主張する。
本発明は、転写調節因子HIF−1アルファのsiRNA誘導分解による遺伝子発現の調節に関するものである。特にVEGF分裂促進性経路における遺伝子を下方制御することができる。
AACTGGACACAGTGTGTTTGA (配列ID番号6)
である。
血管新生を腫瘍部位及びその近傍に誘導することにより、適切な血液供給をそれ自体で発生させる。この腫瘍誘導血管新生は、しばしば腫瘍増殖のために必要とされ、転移性細胞が血流に入り込むことも可能にする。
ヒト胎児由来腎臓293(HEK−293)細胞を、標準成長培地において37℃、5%CO2で一晩、24ウェルプレートにて培養した。次の日、細胞が約50%コンフルエントになったとき、実験細胞及び対照細胞にトランスフェクションを行った。リン酸カルシウム試薬中に混合された25mMヒトHIF−1アルファsiRNAを実験細胞にトランスフェクトした。対照細胞はsiRNAを欠くトランスフェクション試薬で処理するか、あるいはリン酸カルシウムトランスフェクション試薬中の25mM非特異的siRNA(EGFP1 siRNA)で処理した。実験細胞について、ヒトHIF−1アルファmRNAを標的とする20個の異なるsiRNAをテストした。これらの抗HIF−1アルファsiRNAは、表2に挙げられた標的配列を含み、すべてのsiRNAは各鎖に3'TTを含んでいた。表2中、「サンプル番号」は図1及び2に示された実験細胞サンプルに対応する。
て、対照及び実験HEK−293細胞を低酸素に導入した。トランスフェクション48時間後、すべてのウェルから細胞培地を取り除き、ヒトVEGF ELISA(R&D systems,ミネアポリス,ミネソタ州)をQuantikineヒトVEGF ELISAプロトコルに記載されている通りに行った。ELISAの結果はAD340プレートリーダー(Beckman Coulter)で読み出され、その結果を図1に示す。
成体(8〜15週齢)メスC57B1/6マウス(n=7)をアベルチン(2,2,2−トリブロモエタノール)で麻酔し、1%のトロピカミドで瞳孔を拡張した。ダイオードレーザー光凝固装置(IRIS Medical,マウンテンビュー,カリフォルニア州)、及びコンタクトレンズとしてカバースリップを備えたスリットランプシステムを使用し、左右相称にレーザー光凝固術を施した。レーザー光凝固術(140mW;75ミクロンスポットサイズ;0.1秒持続時間)を視神経から2〜3ディスク直径の所で、両眼の9時、12時、3時の位置に施した。ブルーフ膜の破裂は有意な脈絡膜新生血管形成(CNV)を作るために必要であるため、ブルーフ膜の破裂のしるしとしてレーザー光凝固時における気泡形成が用いられた。ブルーフ膜の破裂を誘導しないレーザー噴射は本研究から除外した。
5’−cuaacuggacacaguguguTT‐3'(配列ID番号298)
3’−TTgauugaccugugucacaca‐5' (配列ID番号299)
レーザー光凝固から12日後、網膜/脈絡膜血管系を標識するために高分子量のデキストラン−フルオレセイン(Molecular Probes,ユージーン,オーランド州)を灌流し、眼を摘出した。各CNV領域を脈絡膜フラットマウント調製物において測定した。
Claims (32)
- センスRNA鎖及びアンチセンスRNA鎖を含有する単離siRNAであって、該センスRNA鎖及びアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトHIF−1アルファmRNAにおける19個〜25個の連続ヌクレオチドの標的配列と同一であるヌクレオチド配列を有するものであり、前記標的配列は、配列ID番号40、201、223、及び237から成る群から選択されるものである、単離siRNA。
- 請求項1に記載のsiRNAにおいて、該ヒトHIF−1アルファmRNAは配列番号1である、siRNA。
- 請求項1に記載のsiRNAにおいて、該センスRNA鎖は1RNA分子を含有し、アンチセンスRNA鎖は1RNA分子を有するものである、siRNA。
- 請求項1に記載のsiRNAにおいて、RNA二本鎖を形成している該センスRNA鎖及び該アンチセンスRNA鎖は、一本鎖ヘアピンにより共有結合しているものである、siRNA。
- 請求項1に記載のsiRNAにおいて、該siRNAは更に、非ヌクレオチド物質を有するものである、siRNA。
- 請求項1に記載のsiRNAにおいて、該センスRNA鎖及び該アンチセンスRNA鎖は、ヌクレアーゼ分解に対して安定である、siRNA。
- 請求項1に記載のsiRNAであって、更に3’オーバーハングを有するものである、siRNA。
- 請求項7に記載のsiRNAにおいて、該3’オーバーハングは、1〜6個のヌクレオチドを有するものである、siRNA。
- 請求項7に記載のsiRNAにおいて、該3’オーバーハングは、2個のヌクレオチドを有するものである、siRNA。
- 請求項4に記載のsiRNAにおいて、該センスRNA鎖は第1の3’オーバーハングを有し、該アンチセンスRNA鎖は第2の3’オーバーハングを有するものである、siRNA。
- 請求項10に記載のsiRNAにおいて、該第1及び第2の3’オーバーハングはそれぞれ1〜6個のヌクレオチドを有するものである、siRNA。
- 請求項11に記載のsiRNAにおいて、該第1の3’オーバーハングはジヌクレオチドを含有し、該第2の3’オーバーハングはジヌクレオチドを有するものである、siRNA。
- 請求項12に記載のsiRNAにおいて、該第1及び第2の3’オーバーハングを含有する該ジヌクレオチドは、ジチミジル酸(TT)又はジウリジル酸(uu)である、siRNA。
- 請求項7に記載のsiRNAにおいて、該3’オーバーハングはヌクレアーゼ分解に対して安定である、siRNA。
- 請求項1に記載のsiRNAを有する網膜色素上皮細胞。
- センスRNA鎖及びアンチセンスRNA鎖を含有するsiRNAを発現する核酸配列を含有する組換えプラスミドであって、該センスRNA鎖及びアンチセンスRNA鎖は二本鎖RNAを形成し、該センスRNA鎖はヒトHIF−1アルファmRNAにおける19個〜25個の連続ヌクレオチドの標的配列と同一であるヌクレオチド配列を有するものであり、前記標的配列は、配列ID番号40、201、223、及び237から成る群から選択されるものである、組換えプラスミド。
- 請求項16に記載の組換えプラスミドにおいて、siRNAを発現する該核酸配列は、誘導性プロモータ又は調節性プロモータを有するものである、組換えプラスミド。
- 請求項16に記載の組換えプラスミドにおいて、siRNAを発現する該核酸配列は、ヒトU6 RNAプロモータの調節下でポリT終止配列と操作可能に連結するセンスRNA鎖コード配列と、ヒトU6 RNAプロモータの調節下でポリT終止配列と操作可能に連結するアンチセンスRNA鎖コード配列とを有するものである、組換えプラスミド。
- 請求項18に記載の組換えプラスミドにおいて、該プラスミドはpAAVsiRNAである、組換えプラスミド。
- センスRNA鎖及びアンチセンスRNA鎖を含有するsiRNAを発現する核酸配列を有する組換えウイルス性ベクターであって、該センスRNA鎖及びアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトHIF−1アルファmRNAにおける19個〜25個の連続ヌクレオチドの標的配列と同一であるヌクレオチド配列を有するものであり、前記標的配列は、配列ID番号40、201、223、及び237から成る群から選択されるものである、組換えウイルス性ベクター。
- 請求項20に記載の組換えウイルス性ベクターにおいて、siRNAを発現する該核酸配列は、誘導性プロモータ又は調節性プロモータを有するものである、組換えウイルス性ベクター。
- 請求項20に記載の組換えウイルス性ベクターにおいて、siRNAを発現する該核酸配列は、ヒトU6 RNAプロモータの調節下でポリT終止配列と操作可能に連結するセンスRNA鎖コード配列と、ヒトU6 RNAプロモータの調節下でポリT終止配列と操作可能に連結するアンチセンスRNA鎖コード配列とを有するものである、組換えウイルス性ベクター。
- 請求項20に記載の組換えウイルス性ベクターにおいて、該組換えウイルス性ベクターは、アデノウイルスベクター、アデノ髄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からなる群から選択されるものである、組換えウイルス性ベクター。
- 請求項20に記載の組換えウイルス性ベクターにおいて、該組換えウイルス性ベクターは、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って偽型化されるものである、組換えウイルス性ベクター。
- 請求項23に記載の組換えウイルス性ベクターにおいて、該組換えウイルス性ベクターはアデノ髄伴ウイルスベクターを有するものである、組換えウイルス性ベクター。
- siRNAおよび薬学的に許容し得る担体を含有する薬学的組成物であって、該siRNAはセンスRNA鎖及びアンチセンスRNA鎖を有し、該センスRNA鎖及びアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトHIF−1アルファmRNAにおける19個〜25個の連続ヌクレオチドの標的配列と同一であるヌクレオチド配列を有するものであり、前記標的配列は、配列ID番号40、201、223、及び237から成る群から選択されるものである、薬学的組成物。
- 請求項26に記載の薬学的組成物であって、更に、リポフェクチン、リポフェクタミン(lipofectamine)、セルフェクチン(cellfectin)、ポリカチオン(polycation)、又はリポソームを含有するものである、薬学的組成物。
- 請求項16に記載のプラスミド、またはその生理学的に許容し得る塩類、及び薬学的に許容し得る担体を含有する薬学的組成物。
- 請求項28に記載の薬学的組成物であって、更に、リポフェクチン、リポフェクタミン(lipofectamine)、セルフェクチン(cellfectin)、ポリカチオン(polycation)、又はリポソームを有するものである、薬学的組成物。
- 請求項20に記載のウイルス性ベクター及び薬学的に許容し得る担体を有する薬学的組成物。
- 請求項1に記載のsiRNAにおいて、該siRNAは更に変性RNAを有するものであり、前記変性RNAは修飾され、ヌクレアーゼ消化に対して抵抗性を示すものであり、又は前記siRNAは置換若しくは修飾され、1若しくはそれ以上のデオキシリボヌクレオチド塩基を含有するものである、siRNA。
- センスRNA鎖及びアンチセンスRNA鎖を含有する単離siRNAであって、該センスRNA鎖及びアンチセンスRNA鎖はRNA二本鎖を形成し、該センスRNA鎖は、ヒトHIF−1アルファmRNAにおける19個〜25個の連続ヌクレオチドの標的配列と同一であるヌクレオチド配列を有するものであり、前記標的配列は、配列ID番号223を有するものである、単離siRNA。
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