JP5095403B2 - 治療的応用法のための遺伝的に改変された細胞 - Google Patents
治療的応用法のための遺伝的に改変された細胞 Download PDFInfo
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Description
Topol, E. J. Lancet 357, 1905-1914 (2001) Robbins, M.A. & O’Connell, J.B., pp. 3-13 (Lippincott-Raven, Philadelphia, 1998) Pfeffer, J.M., Pfeffer, M.A., Eletcher, P.J. and Braunwald, E. Am. J. Physiol 260, H1406-H1414 (1991) Pfeffer, M.A. and Braunwald, E. Circulation 81, 1161-1172 (1990) Penn, M.S.et al.Prog. Cardiovasc. Dis. 45, 21-32 (2002) Koh, G.Y., Klug, M.G., Soonpaa, M.H. およびField, L.J. J. C1in. Invest 92, 1548-1554 (1993) Taylor, D.A,et al. Nat. Med. 4, 929-933 (1998) Jain, M, et al. Circulation 103, 1920-1927 (2001) Li, R. K.et al. Ann. Thorac. Surg. 62, 654-660 (1996) Etzion, S.et al. J.Mol.Ce11 Cardiol. 33, 1321-1330 (2001) Li, R. K., Jia, Z.Q., Weisel, R.D., Merante, F. and Mickle, D.A. J. Mol. Cell Cardiol. 31, 513-522 (1999) Yoo, K. J.et al. Yonsei Med. J. 43, 296-303 (2002) Sakai, T.et al. Ann. Thorac. Surg. 68, 2074-2080 (1999) Sakai, T. et al. J. Thorac. Cardiovasc. Surg. 118, 715-724 (1999) Orlic, D.et al. Nature 410, 701-705 (2001) Tomita, S.et al. J. Thorac. Cardiovasc. Surg. 123, 1132-1140 (2002) Jackson, K.A.et al. J. Clin. Invest 107, 1395-1402 (2001) Quaini, F.et al. N. Engl. J. Med. 346, 5-15 (2002) Kocher, A.A.et al. Nat. Med. 7, 430-436 (2001) Orlic, D.et al. Proc. Natl. Acad. Sci. U. S. A 98, 10344-10349 (2001) Peled, A.et al. Blood 95, 3289-3296 (2000) Yong, K.et al. Br. J. Haematol. 107, 941-449 (1999)
本発明の1つの態様では、MSC、MAPC、および/またはその他の幹細胞を、CXCケモカイン受容体4(CXCR4)を過剰発現するように遺伝的に改変することができる。CXCR4は、CD184、白血球由来7回膜貫通ドメイン受容体(LESTR)、ニューロペプチドY受容体Y3(NPY3R)、HM89、FB22、としても知られており、ストローマ細胞由来因子−1(SDF1)と呼ばれる単一CXCモチーフ型ケモカインに対する選択性をもつ、Gタンパク質結合受容体である。CXCR4は、成熟赤血球および赤血球前駆細胞における走化作用を仲介し、そのリガンドSDF−1と共に、Bリンパ球分化および骨髄造血に不可欠である。CXCR4はまた、造血に加え、心臓の心室中隔形成、胃腸管の血管新生および小脳における顆粒細胞の発生をつかさどる。
本発明に係る過剰発現されるCXCR4はまた、例えば、哺乳動物のCXCR4の断片、類似体、および誘導体等の、哺乳動物CXCR4の変異体であってもよい。このような変異体の例としては、例えば、天然CXCR4遺伝子の天然対立遺伝子変異体によってコードされるポリペプチド(すなわち、天然哺乳動物CXCR4ポリペプチドをコードする天然核酸)、天然CXCR4遺伝子の選択的スプライシング型によりコードされるポリペプチド、天然CXCR4遺伝子のホモログまたはオーソログによってコードされるポリペプチド、および、天然CXCR4遺伝子の非天然変異体によりコードされるポリペプチド、が挙げられる。
本発明の別の態様によれば、MSC、MAPC、および/またはその他の幹細胞を、ストローマ細胞由来因子−1(SDF−1)を過剰発現するように遺伝的に改変することができる。CXCケモカインL12としても知られているSDF−1は、ケモカインCXCファミリーのメンバーで、CXCR4の天然のリガンドであると考えられている。SDF−1は、骨髄前駆細胞の輸送、搬出、およびホーミング(homing)において基本的な役割を果たすことが報告されているという点で、他のケモカインとは機能的に異なっている。さらに、SDF−1は、他のCXCケモカインとのアミノ酸配列同一性がわずか約22%という点で、構造上独特である。SDF−1が基本的な生理学的役割を果たしていることは、SDF−1配列が複数の種の間で高度に保存されていることからも示唆される。in vitroでは、SDF−1は、単球や骨髄由来前駆細胞を含む、様々な細胞の走化性を刺激する。
SDF−1ポリペプチド変異体はまた、組換え型のSDF−1ポリペプチドを含んでもよい。SDF−1ポリペプチドに加え、本発明における好ましい組換え型ポリペプチドは、哺乳動物のSDF−1をコードする遺伝子の核酸配列と少なくとも約70%の配列同一性を持つことができる核酸によってコードされる。
本発明の範囲内におけるSDF−1をコードするその他の核酸分子は、例えば、天然SDF−1ポリペプチドの断片、類似体、および、誘導体をコードするような、天然SDF−1タンパク質の変異体である。このような変異体としては、例えば、天然SDF−1遺伝子の天然対立遺伝子変異体、天然SDF−1遺伝子のホモログもしくはオーソログ、または、天然SDF−1遺伝子の非天然変異体、が挙げられる。これらの変異体は、1個以上の塩基において天然SDF−1遺伝子とは異なる塩基配列を有する。例えば、このような変異体の塩基配列は、天然SDF−1遺伝子の1個以上のヌクレオチドの欠失、付加、または、置換を有してもよい。核酸の挿入は、約1〜10個の連続するヌクレオチドであることが好ましく、欠失は、約1〜10個の連続するヌクレオチドであることが好ましい。
本発明のまた別の態様によれば、MSC、MAPC、および/またはその他の幹細胞は、CXCR4とSDF−1の両者を過剰発現するように遺伝的に改変することができる。本発明に従って過剰発現されるCXCR4ポリペプチドは、哺乳動物CXCR4ポリペプチドのアミノ酸配列に実質的に類似のアミノ酸配列を有することができる。例えば、過剰発現されるCXCR4は、配列番号1および/または配列番号2に実質的に類似のアミノ酸配列を有することができる。また、過剰発現させるSDF−1も、哺乳動物SDF−1のアミノ酸配列と実質的に同一のアミノ酸配列を有することができる。例えば、過剰発現されるSDF−1は、配列番号5、配列番号6、および/または配列番号7と実質的に同一のアミノ酸配列を有することができる。
また、MSC、MAPC、および/またはその他の幹細胞からのCXCR4およびSDF−1の発現を促進するため、他の薬剤を、これらの幹細胞に導入することもできる。例えば、CXCR4およびSDF−1をコードする遺伝子の転写を増加させる薬剤は、CXCR4およびSDF−1をコードするmRNAの翻訳を増加させる。その上/あるいは、CXCR4およびSDF−1をコードするmRNAの分解を減少させる薬剤を、CXCR4およびSDF−1を過剰発現させるために用いることも可能である。細胞内の遺伝子からの転写率は、CXCR4をコードする遺伝子およびSDF−1をコードする遺伝子の上流に外因性プロモーターを導入することにより、高めることができる。異種遺伝子の発現を促進するエンハンサーエレメントも使用してよい。
CXCR4、SDF−1、またはCXCR4とSDF−1の両者を過剰発現するように遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞は、組織および/または臓器系の拡張、再増殖、保存、および/または再生が望ましい場合の、潜在的にいかなる細胞療法や治療的応用法にも用いることが可能である。本発明の1つの態様によれば、CXCR4を過剰発現するように遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞は、最近心筋梗塞またはうっ血性心不全を罹患した患者を治療するために使用することができる。最近心筋梗塞またはうっ血性心不全を罹患した患者は、遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞を、梗塞した心筋組織および/または梗塞した心筋組織に隣接する組織に送達することにより、治療することができる。梗塞した心筋組織に送達された遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞は、細胞に分化することができ、その細胞が再増殖し(すなわち、生着し)、梗塞した心筋の正常な機能を部分的または全面的に回復させることができる。
別の方法として、心筋の構造を再生するために用いる遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞は、これらの遺伝的に改変された幹細胞を、治療対象の哺乳動物被験体中へ静脈注入または動脈注入することにより、梗塞した心筋組織に送達することができる。心筋の構造を再生するために用いる、SDF−1および/またはCXCR4を過剰発現しているMSC、MAPC、および/またはその他の幹細胞の注入は、心筋梗塞の後間もなく(例えば、約1日後)に行うことができる。心筋梗塞が起こると、梗塞した心筋組織中で、SDF−1の発現が一時的にアップレギュレートする。SDF−1の発現がこのようにアップレギュレートすると、哺乳動物被験体の末梢血に注入する、心筋の構造を再生するために用いる遺伝的に改変されたMSC、MAPC、および/またはその他の幹細胞が、梗塞した心筋組織にホーミングできるようになる。心筋の構造を再生するために用いるMSC、MAPC、および/またはその他の幹細胞からのCXCR4および/またはSDF−1の過剰発現は、遺伝的に改変された幹細胞の生存率を向上させ、その結果、当該療法の治療効果が高められる。
CXCR4を発現するようMSCを遺伝的に改変することが、梗塞した心筋へのMSCのホーミングおよびその生存率に対して影響を与えるかどうかを確認するため、200万個の、MSCおよびCXCR4を発現するように遺伝的に改されたMSCを、左上行動脈の結紮により心筋梗塞を促進して1日後のラットに、静脈注入した。図2は、MSC、およびCXCR4を発現するように遺伝的に改変されたMSCを注入3日後の、梗塞域中における、MSCおよび遺伝的に改変されたMSCの単位面積当たりの数を示す。
CXCR4またはSDF−1を発現するようMSCを遺伝的に改変することが、梗塞した心筋において、MSCに対し抗アポトーシス効果を発揮する(すなわち、MSCのアポトーシスを抑制するかまたは阻害する)かどうかを調べるため、MSC、およびCXCR4またはSDF−1をトランスフェクトしたMSCについて、AKTおよびリン酸化AKTに関するウエスタンブロット解析を行った。図3は、CXCR4またはSDF−1を発現するよう安定的にトランスフェクトしたラットMSCのAKTが、トランスフェクトしていないMSCのAKTと比較して、容易にリン酸化されたことを示す。AKTのリン酸化は、MSCのアポトーシスを阻害することが知られている。
CXCR4を発現するようMSCを遺伝的に改変することが、梗塞した心筋へのMSCのホーミングおよびその生存率に対して影響を与えるかどうかを評価するため、MSC、およびCXCR4またはSDF−1を発現するように遺伝的に改変されたMSCをそれぞれ、LAD結紮による心筋梗塞後の各ラット個体に静脈注入した。
図4Bは、注入3日後の、単位面積当たりの梗塞域中のコントロールMSCの数を、CXCR4またはSDF−1を発現するように遺伝的に改変されたMSCの数と比較したものである。
図4Aおよび4Bの両者から分かるように、単位面積当たりの遺伝的に改変されたMSCの数は、コントロールMSCの数より実質的により多かった。このことは、CXCR4またはSDF−1を発現しているMSCが、遺伝的に改変されていないMSCと比較して、生存率もホーミングも向上したことを示している。
コントロールMSC、およびSDF−1を発現しているMSCにより治療した、各ラットの梗塞域を調べた。
図5は、心筋梗塞4日後の各梗塞域の写真である。これらの写真は、SDF−1を発現しているMSCが、生存している心筋組織中のアポトーシスを減少させることを示している。
CXCRを発現するようMSCを遺伝的に改変することが、梗塞した心筋へのMSCのホーミングおよびその生存率に対して影響を与えるかどうかを確認するため、MSC、およびCXCR4またはSDF−1をそれぞれ発現するように遺伝的に改変されたMSCを、LAD結紮による心筋梗塞1日後の各ラット個体に静脈注入した。
Claims (2)
- SDF−1、またはSDF−1とCXCR4を発現するように遺伝的に改変された単離間葉系幹細胞を含む、医薬組成物。
- SDF−1、またはSDF−1とCXCR4を発現するように遺伝的に改変された単離間葉系幹細胞を含む、心筋梗塞の治療剤。
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CA2567177A1 (en) | 2005-12-08 |
EP1763538B1 (en) | 2010-08-25 |
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