JP5513885B2 - ポリペプチド、および、当該ポリペプチドをコードするポリヌクレオチド、および、虚血に関連する医学的状態の治療におけるそれらの使用 - Google Patents
ポリペプチド、および、当該ポリペプチドをコードするポリヌクレオチド、および、虚血に関連する医学的状態の治療におけるそれらの使用 Download PDFInfo
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Description
三重変異型HIF−1αはP402A/P564GおよびP564A/N803Aの二重変異体よりも大きい転写活性を示す
HIF−1α内のP402AおよびP564Gの点変異は、腫瘍抑制因子VHLとのその相互作用を阻止し、従って、これにより、その後のそのプロテオソーム分解を妨げることが以前に示された。これは、低酸素状態に匹敵し得る活性レベルに達する正常酸素圧時における安定化されたHIF−1αをもたらした。同様に、P564A/N803Aの点変異を伴うHIF−1αは、低酸素模倣鉄キレート剤の2,2’−ジピリジルによる処置の後、正常酸素圧において、野生型HIF−1αと同じくらい活性であることが明らかにされた。本発明者らは、3つすべての変異の組合せにより、P402A/P564Gの変異体よりも活性であり、かつ、P564A/N803Aの変異体よりも安定であり、従って、これにより、治療的血管形成の目的のためにより効き目のあるものにする、「三重変異体」と呼ばれる変異されたHIF−1αがもたらされるかもしれないことを仮定した。
細胞培養:下記の細胞株を使用した。ウシの大動脈内皮細胞(BAEC)をN.Savion(Goldschleger Eye Institute、Sheda Medical Center)から譲り受けた。ヒトの胚性腎臓細胞(HEK293細胞)をAmerican Type Culture Collection(Rockville、Maryland、米国)から購入した。20回−26回継代した293細胞を使用した。HeLa細胞をY.Keisary(Tel Aviv大学)から譲り受けた。ヒトの臍帯静脈EC(HUVEC)を以前の記載[Jaffe,E.A.ら、J Clin Invest、52、2745−56(1973)]のように購入した。腎細胞癌(RCC)細胞をG.Lavi(Angiogenesis Institute、Sheda Medical Institute)から譲り受けた。BAEC、HEK293細胞およびRCCを、10%のFCS、2mMのグルタミンおよび100U/mlのペニシリン/ストレプトマイシンが補充されたDMEMで培養した。HeLa細胞を、10%のFCSおよび100U/mlのペニシリン/ストレプトマイシンが補充されたMEMで培養した。HUVECをEGM−2および2%FCS(Clonetics、San−Diego、California、米国)において維持した。すべての細胞を37℃において5%CO2の加湿インキュベーターで維持した。
ヒト胚性腎臓293細胞(HEK293)およびウシ大動脈内皮細胞(BAEC)の両方において、一過性トランスフェクションされた三重変異型HIF−1αは、P402A/P564GおよびP564A/N803Aの二重変異体と比較して、正常酸素圧において転写活性における2倍−2.5倍の増大を示した(図1A−図1B)。
C−トランス活性化ドメインの活性化が最適なHIF−1α媒介の血管形成のために不可欠である。
三重変異体の増大した転写能力の意味を治療的血管形成に関して評価するために、異なる変異体の比較を、ヒト臍帯静脈内皮細胞(HUVEC)において、HIF−1α構築物のトランスフェクションの後、インビトロ血管形成アッセイを使用して行った。
インビトロ血管形成アッセイ:60mmディッシュで成長させたトランスフェクションHUVECまたは感染HUVECをEGM−2培地で24時間維持し、その後、EBM−2と培地交換した。細胞をアッセイ前にEBM−2においてさらに24時間維持した。その後、細胞をトリプシン処理し、増殖因子低減マトリゲル(BD Biosciences、米国)により事前に被覆された24ウエルプレートにウエルあたり50000細胞の濃度で播種した。毛細管および管の形成を8時間追跡した。毛細管形成の定量化を、5つの無作為の顕微鏡視野において高倍率顕微鏡視野あたりの毛細管分岐の数を計数することによって行った。
空ベクターは管形成を何ら引き起こさなかった一方で、すべてのHIF−1α構築物、VEGF陽性コントロールおよびFCS陽性コントロールは血管形成を刺激した(図2A−図2F)。野生型HIF−1αおよびP402A/P564Gは、類似する程度に管形成を刺激したが、両者は、P564A/N803Aおよび三重変異体と比較して、著しく低下した血管形成作用を有していた(p<0.001)(図2G)。これらの知見と一致して、wt−HIF1αまたはP402A/P564Gによる処理の後でのHUVECにおけるVEGFタンパク質濃度は非常に類似し、P564A/N803Aまたは三重変異体による処理よりも著しく低かった(p=0.029)(図2H)。P564A/N803Aまたは三重変異体による処理は、wt−HIF1αおよびP402A/P564Gと比較して、VEGFタンパク質における6倍の増大および10倍の増大をそれぞれもたらした(図2H)。これらの結果は、HIF−1αの安定性が不十分であること、および、構成的に活性なC−TADがHIF−1αの最大血管形成作用のために不可欠であることを示している。違いが、P564A/N803Aと、三重変異体との間には何ら認められなかった。これは、高いHIF−1αの過剰発現に起因し得る。それは、ヒドロキシラーゼ酵素を飽和させ、従って、これにより、安定性に起因する何らかの違いを隠した。これは、図1DにおいてRCC内に見出される状態に類似している。
虚血におけるPPE−1−3xプロモーターの発現および特異性
全身的な前血管形成遺伝子治療の実現可能性および安全性のための前提条件は、標的の虚血組織の内部での十分にロバストかつ特異的な発現である。虚血の状況における修飾PPE−1プロモーターの発現および特異性を特徴づけるために、GFPをPPE−1−3xの調節下で発現するアデノウイルスを使用した(Ad−PPE−1−3x−GFP)。
アデノウイルスベクターの構築:Ad−PPE−Triple、Ad−CMV−TripleおよびAd−CMV−wtの各ベクターを、Vector Biolabs(Philadelphia、米国)による相同的組換えによって作製した。ウイルス構築物の成功した作製をPCRによって確認し、その後、2回のプラーク精製を行った。ウイルスプラークは引き続いてHEK293における大規模精製を受け、その後、CsCl精製が行われた。
マウスは大腿動脈の結紮による後肢虚血を受けたか、または、擬似手技を受け、その後、Ad−PPE−1−3x−GFPが筋肉内注入された。コントロール動物には、Ad−CMV−GFPまたは生理的食塩水が注入された。Ad−CMV−GFP注入後のGFP発現が、虚血性筋肉および非虚血性筋肉の筋細胞および内皮細胞の両方で筋肉の組織学的切片において検出された。対照的に、Ad−PPE−1−3x−GFP注入後のGFP発現が虚血性筋肉の内皮細胞において検出され、一方で、発現が非虚血性筋肉では特定されなかった。これらの結果により、修飾されたPPE−1プロモーターの、内皮および虚血状態に対する特異性が明らかにされる。
Ad−PPE−Triple HIF−1αの局所的注入は虚血の血管新生を増強する
下記の実験を、PPE−1−3xプロモーターの発現のもとでのアデノウイルス媒介の三重変異型HIF−1αによる筋肉内処置が血管形成をインビボで促進させ得るかどうかを明らかにするために行った。
後肢血流のモニタリング:マウスを麻酔し、体温変動を最小限に抑えるために37℃での加熱プレートに5分間置いた。後肢血流を、手術直後、ならびに、手術後7日目、14日目、21日目および28日目に、レーザードップラー灌流画像化装置システム(Moor Instruments Ltd.、英国)を用いて測定した。低い灌流および/または無灌流のシグナルが青色で表示され、これに対して、最高灌流のシグナルが赤色で表示された。カラー写真を記録し、分析を、虚血性後肢および非虚血性後肢の平均灌流を計算することによって行った。変数(例えば、周囲の光および温度など)を補償するために、結果が、右側(非虚血)後肢に対する左側(虚血)後肢における灌流の比率として表される。
後肢の虚血をマウスにおいて誘導し、その後、Ad−PPE−1−3x−Triple、Ad−CMV−TripleまたはAd−CMV−wtの筋肉内注入を行った。コントロール動物には、Ad−CMV−Lucまたは生理的食塩水を注入した。血流、臨床的結果、および、血管形成の指標を28日の期間にわたって調べた。手術直後、虚血肢における血流がすべてのマウス群において正常な肢の10%未満に低下した。21日目までに、Ad−CMV−TripleまたはAd−PPE−1−3x−Tripleにより処置されたマウスは、Ad−CMV−wt、Ad−CMV−Lucまたは生理的食塩水コントロールにより処置されたマウスと比較して、後肢血流の著しい増大を示した(図4A)。28日目までに、Ad−CMV−TripleおよびAd−PPE−1−3x−Tripleはともに、虚血肢における灌流を正常な肢のおよそ50%に改善し、これらは、Ad−CMV−wtまたはコントロールの処置よりも著しく大きかった(図4A−図4B)。そのうえ、Ad−CMV−TripleまたはAd−PPE−Tripleによる処置は、虚血肢に対する血流の改善と一致して、虚血誘導の足指の壊死および自切(これらは、Ad−CMV−wtまたはコントロールにより処置されたマウスでは顕著であった)を完全に低下させることができた(図4C−図4D)。血流の知見と一致して、CD31染色後の筋肉の毛細管密度の定量化では、毛細管対筋繊維の比率が、Ad−CMV−Triple処置動物およびAd−PPE−1−3x−Triple処置動物では、Ad−CMV−wt処置動物およびコントロール処置動物よりも大きいことが明らかにされた(図4Eおよび図4F)。
Ad−PPE−1−3x−Tripleの全身投与は、Ad−CMV−Tripleと比較して、より安全であり、また、副作用を全く示さない
下記の実験を、Ad−PPE−1−3x−Tripleの全身投与の安全性プロフィルをAd−CMV−Tripleの全身投与の安全性プロフィルと比較するために行った。アデノウイルスのほとんどが注入部位に集中する局所的な筋肉内注入とは対照的に、尾静脈を介する静脈内投与の後では、アデノウイルスのほとんどが肝臓に到達し、形質導入する。従って、処置の安全性にかかわらず、マウスにおいて発生する肝臓機能における何らかの変化および他の全身的症状発現をモニターすることは特に重要であった。
血清ビリルビン、血清ASTおよび血清ALTの測定:マウス血清を注入後5日目および21日目で得て、自動分析計を使用して分析した。
後肢の虚血を受けたマウスに、Ad−PPE−1−3x−Triple、Ad−CMV−TripleおよびAd−CMV−wtが、手術後7日で尾静脈を介して全身に注入され、一方で、Ad−CMV−Lucまたは生理的食塩水がコントロールとして役立った。注入後1日で、生理的食塩水により処置されたマウスを除くマウスのすべての群が体重における顕著な低下を示した。しかしながら、すべての他のアデノウイルス処置マウスが注入後3日目までにそれらの元の体重を回復したが、Ad−CMV−Triple処置マウスは、4日目までに最大で10%の低下に達する体重の低下を続けた(図5A)。このことは全身的な障害を示している。マウスの肝臓機能検査を注入後5日で行った。検査では、生理的食塩水コントロールを上回る、Ad−CMV−Triple処置マウスにおける顕著な25倍の血清ビリルビンの増大が明らかにされた。このことは重度の黄疸を明らかにする。Ad−CMV−wtは、血清ビリルビンのより穏やかな増加を引き起こした(図5C)。さらに、血清ASTレベルおよび血清ALTレベルが、Ad−CMV−Triple処置マウス、Ad−CMV−wt処置マウス、および、同様にAd−CMV−Luc処置マウスでは5日目までに大きく上昇した(図5Bおよび図5D)。Ad−CMV−Triple処置マウスによって示される肝障害の明白な全身的症状発現とは対照的に、Ad−PPE−Tripleにより処置されたマウスは障害の徴候を何ら示さず、その血清ビリルビンレベル、血清ASTレベルおよび血清ALTレベルは生理的食塩水処置マウスと同程度であった。これらの知見と一致して、5日目で屠殺されたマウスの肝臓の組織学的切片は、著しい炎症およびリンパ球浸潤をAd−CMV−Triple処置マウスにおいて明らかにし、一方で、Ad−PPE−1−3x−Triple、Ad−CMV−Lucおよび生理的食塩水コントロールは病理を何ら示さなかった(図5E−図5N)。軽度のリンパ球浸潤が同様に、Ad−CMV−wt処置群において認められた。肝臓病理のこの急性期の後、Ad−CMV−Triple処置マウスは、徐々ではあるが、部分的回復を示した。Ad−CMV−Triple処置マウスはその体重を回復し、また、注入後28日目までに、その血清ビリルビンが正常に戻っていた。しかしながら、その血清ASTおよび血清ALTは、Ad−CMV−wt群およびAd−CMV−Luc群と同様に、Ad−PPE−1−3x−Triple処置マウスおよび生理的食塩水コントロール処置マウスと比較した場合、依然として上昇していた。この部分的な肝臓回復はまた、注入後21日目から得られる肝臓の組織学的切片でも見られた(図5E−図5N)。このことは、軽度のリンパ球浸潤が、Ad−CMV−tripleにより処置された動物において残っていることを示す。
配列番号2は、三重変異HIF−1αの配列である。
配列番号4は、PPE−1プロモーターの配列である。
配列番号5は、低酸素応答エレメントの配列である。
配列番号6〜15は、一本鎖DNAオリゴヌクレオチドの配列である。
Claims (28)
- 配列番号4の少なくとも一つのコピーを含む、内皮細胞特異的プロモーター。
- ポリペプチドをコードする遺伝子に機能的に連結されている、請求項1に記載の内皮細胞特異的プロモーター。
- 請求項1の内皮細胞特異的プロモーターと、ポリペプチドをコードするヌクレオチド配列とを含む、組換えポリヌクレオチド。
- ポリペプチドがH1F−α活性を有する、請求項3に記載のポリヌクレオチド。
- ポリペプチドが、配列番号3に対して少なくとも90%の同一性を有するアミノ酸配列を含む、請求項4に記載のポリヌクレオチド。
- ポリヌクレオチドが、配列番号3のプロリン402に対応する位置での変異、配列番号3の564におけるプロリンに対応する位置での変異、又は配列番号3のアスパラギン803に対応する位置での変異を含む、請求項5に記載のポリヌクレオチド。
- ポリヌクレオチドが、配列番号3のプロリン402に対応する位置での変異、配列番号3の564におけるプロリンに対応する位置での変異、及び配列番号3のアスパラギン803に対応する位置での変異を含む、請求項6に記載のポリヌクレオチド。
- 配列番号3のプロリン402に対応する位置での変異がアラニンへの変異であり、配列番号3の564におけるプロリンに対応する位置での変異がグリシンへの変異であり、又は配列番号3のアスパラギン803に対応する位置での変異がアラニンへの変異である、請求項6に記載のポリヌクレオチド。
- 配列番号3のプロリン402に対応する位置での変異がアラニンへの変異であり、配列番号3の564におけるプロリンに対応する位置での変異がグリシンへの変異であり、及び配列番号3のアスパラギン803に対応する位置での変異がアラニンへの変異である、請求項8に記載のポリヌクレオチド。
- ポリペプチドが配列番号2を含む、請求項3に記載のポリヌクレオチド。
- ヌクレオチド配列が配列番号1を含む、請求項3に記載のポリヌクレオチド。
- 請求項1もしくは2に記載の内皮細胞特異的プロモーター、又は請求項3〜11のいずれかに記載のポリヌクレオチドを含むベクター。
- 原核生物のベクター又は真核生物のベクターである、請求項12に記載のベクター。
- アデノウイルスである、請求項13に記載のベクター。
- 請求項1もしくは2に記載の内皮細胞特異的プロモーター、又は請求項3〜11のいずれかに記載のポリヌクレオチドを含む細胞。
- 請求項3〜11のいずれかに記載のポリヌクレオチドによってコードされるアミノ酸配列を含む組換えポリペプチド。
- 請求項3〜11のいずれかに記載のポリヌクレオチド、及び医薬的に許容され得るキャリアを含む医薬組成物。
- 請求項12〜14のいずれかに記載のベクター、及び医薬的に許容され得るキャリアを含む医薬組成物。
- 請求項16に記載の組換えポリペプチド、及び医薬的に許容され得るキャリアを含む医薬組成物。
- 必要性のある対象の内皮細胞に対してポリペプチドの内皮細胞特異性を付与するための医薬の製造のための請求項2に記載の内皮細胞特異的プロモーターの使用。
- 血管新生関連疾患に関連する症状を予防、緩和、又は軽減させるための医薬の製造のための請求項3〜11のいずれかに記載のポリヌクレオチドの使用。
- 対象がヒトである、請求項21に記載の使用。
- 毛細血管密度を必要性のある対象において増大させるための医薬の製造のための請求項3〜11のいずれかに記載のポリヌクレオチドの使用。
- 低酸素又は虚血に関連する医学的状態を必要性のある対象において治療するための医薬の製造のための請求項3〜11のいずれかに記載のポリヌクレオチドの使用。
- 全身投与又は局所投与のために処方される、請求項24に記載の使用。
- 経口投与、直腸投与、経粘膜投与、経鼻投与、腸管投与、非経口投与、筋肉内投与、皮下投与、髄内投与、クモ膜下投与、直接的な脳室内投与、静脈内投与、腹腔内投与、鼻内投与又は眼内投与のために処方される、請求項25に記載の使用。
- 低酸素又は虚血に関連する医学的状態が、創傷治癒、虚血性卒中、虚血性心疾患、末梢血管疾患、腎動脈疾患、胃腸病変、火傷、皮膚移植、血管移植、臓器修復、骨修復障害、肝臓障害、子宮障害、眼の血管形成障害、骨再生障害、軟骨修復障害及び平滑筋細胞障害からなる群から選択される、請求項24に記載の使用。
- 対象がヒトである、請求項27に記載の使用。
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