JP5260272B2 - 混合細胞遺伝子治療 - Google Patents
混合細胞遺伝子治療 Download PDFInfo
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- JP5260272B2 JP5260272B2 JP2008334092A JP2008334092A JP5260272B2 JP 5260272 B2 JP5260272 B2 JP 5260272B2 JP 2008334092 A JP2008334092 A JP 2008334092A JP 2008334092 A JP2008334092 A JP 2008334092A JP 5260272 B2 JP5260272 B2 JP 5260272B2
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Description
Mankinら、J Bone Joint Surg, 52A: 460-466, 1982 Ozkaynakら、EMBO J, 9:2085-2093, 1990 Sampath及びRueger、Complications in Ortho, 101-107, 1994 Joyceら、J Cell Biology, 110:2195-2207, 1990 Sporn及びRoberts、Nature (London), 332:217-219, 1988 Madriら、J Cell Biology, 106: 1375-1384, 1988 Chenuら、Proc Natl Acad Sci, 85: 5683-5687, 1988 Critchlowら、Bone, 521-524, 1995 Lindら、A Orthop Scand, 64(5): 553-556, 1993 Matsumotoら、In vivo, 8:215-220, 1994 Joyceら、J Cell Biology, 110: 2195-2207, 1990 Miettinenら、J Cell Biology, 127-6: 2021-2036, 1994 Andrew et al., Calcif Tissue In. 52: 74-78, 1993 Borque et al., Int J Dev Biol., 37:573-579, 1993 Carrington et al., J Cell Biology, 107:1969-1975, 1988 Brittbergら、New Engl J Med 331:889-895, 1994 Wolff及びLederberg, Gene Therapeutics ed. Jon A. Wolff, 3-25, 1994 Jenks, J Natl Cancer Inst, 89(16): 1182-1184, 1997 Leeら「ヒト遺伝子治療」12: 1085-1813, 2001
細胞は、公知のプロトコールを利用して解凍してよい。冷凍及び解凍の継続期間については、細胞の生存能力及び効能が最適化される限り、任意の数の形で実施してよい。
レトロウイルスベクタにおいてクローニングされたTGF−β及びBMP2 cDNAは、線維芽細胞(NIH3T3−TGF−β1及びNIH3T3−BMP−2)及び軟骨細胞(hChon−TGF−β1)に個別に形質導入した。濃度10%のウシ胎仔血清を有するダルベッコ改変イーグル培地(メリーランド州ロックビルのGIBCO−BRL)において、これらを培養した。
体重2.0〜2.5kgのニュージーランドホワイトウサギを動物実験のために選択した。これらのウサギは成熟しており、成長限界に達していた。膝関節を露出し、大腿顆のヒアリン軟骨層において、メスで部分関節欠損(3mm×6mm、深さ1〜2mm)又は全層欠損(3mm×6mm、深さ2〜3mm)を形成した。対照のヒト軟骨細胞(hChon)、或いはhChon及びNIH3T3−TGF−β1細胞又はNIH3T3−BMP−2細胞の混合物のいずれかを、欠損のあるウサギ膝関節に注入した。これらの細胞(2×106細胞/mlの15〜20μl)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。全層欠損を有するウサギにhChon及びNIH3T3−BMP−2細胞の混合物を注入した実験において、こうした混合細胞組成物は、欠損形成の3週間後に、欠損に注入した。大腿顆は、細胞注入の6週間又は12週間後に回収及び検査した。
対照のhChon、或いはhChon及びNIH3T3−TGF−β1細胞を含む混合物のいずれかを、大腿顆に部分軟骨欠損(3mm×5mm、深さ1〜2mm)を含むウサギ膝関節に注入した。細胞の混合物(2×106細胞/mlの15〜20μl、hChonとNIH3T3−TGF−β1との比10:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の6週間後に回収し、顕微鏡により観察した。図3A及び3Cは、hChon及びNIH3T3−TGF−β1細胞の混合物(A)又はhChonのみ(C)のいずれかによる注入の6週間後の大腿顆の写真を示す。図3B及び3Dは、hChon及びNIH3T3−TGF−β1細胞の混合物(B)又はhChonのみ(D)のいずれかによる注入後の大腿顆の断面におけるメイソン三重染色を示す。[オリジナル倍率:(B及びD)12.5倍]
対照のhChon、或いはhChon及びNIH3T3−TGF−β1細胞の混合物のいずれかを、大腿顆に全層軟骨欠損(3mm×5mm、深さ2〜3mm)を含むウサギ膝関節に注入した。細胞混合物(2×106細胞/mlの20〜25μl、hChonとNIH3T3−TGF−β1との比10:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の12週間後に回収し、顕微鏡により観察した。図4A及び4Dは、hChon及びNIH3T3−TGF−β1細胞の混合物(A)又はhChonのみ(D)のいずれかによる注入の12週間後の大腿顆の写真を示す。図4B、4C、及び4Eは、hChon及びNIH3T3−TGF−β1細胞の混合物(B及びC)又はhChonのみ(E)のいずれかによる注入後の大腿顆の断面におけるメイソン三重染色(B及びE)及びサフラニンO染色(C)を示す。[オリジナル倍率:(B、C、及びE)12.5倍]
対照のhChon、或いはhChon及びNIH3T3−BMP−2細胞の混合物のいずれかを、大腿顆に部分軟骨欠損(3mm×5mm、深さ1〜2mm)を含むウサギ膝関節に注入した。細胞混合物(2×106細胞/mlの15〜20μl、hChonとNIH3T3−BMP−2との比10:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の6週間後に回収し、顕微鏡により観察した。図5A及び5Cは、hChon及びNIH3T3−BMP−2細胞の混合物(A)又はhChonのみ(C)のいずれかによる注入の6週間後の大腿顆の写真を示す。図5B及び5Dは、hChon及びNIH3T3−BMP−2細胞の混合物(B)又はhChonのみ(D)のいずれかによる注入後の大腿顆の断面におけるメイソン三重染色を示す。[オリジナル倍率:(B及びD)12.5倍]
対照のhChon、或いはhChon及びNIH3T3−BMP−2細胞の混合物のいずれかを、大腿顆に全層軟骨欠損(3mm×5mm、深さ2〜3mm)を含むウサギ膝関節に注入した。このケースにおいて、細胞は、欠損形成の3週間後に注入した。細胞混合物(2×106細胞/mlの20〜25μl、hChonとNIH3T3−BMP−2との比10:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の6週間後に回収し、顕微鏡により観察した。図6A及び6Dは、hChon及びNIH3T3−BMP−2細胞の混合物(A)又はhChonのみ(D)のいずれかによる注入の12週間後の大腿顆の写真を示す。図6B、6C、及び6Eは、hChon及びNIH3T3−BMP−2細胞の混合物(B及びC)又はhChonのみ(E)のいずれかによる注入後の大腿顆の断面におけるメイソン三重染色(B及びE)及びサフラニンO染色(C)を示す。[オリジナル倍率:(B、C、及びE)12.5倍]
対照のヒト軟骨細胞(hChon)、或いはhChon及びhChon−TGF−β1細胞の混合物のいずれかを、大腿顆に全層軟骨欠損(3mm×5mm、深さ2〜3mm)を含むウサギ膝関節に注入した。細胞混合物(2×106細胞/mlの20〜25μl、hChonとhChon−TGF−β1との比1:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の6週間後に回収し、顕微鏡により観察した。図7A及び7Cは、hChon及びhChon−TGF−β1細胞の混合物(A)又はhChonのみ(C)のいずれかによる注入の6週間後の大腿顆の写真を示す。図7B及び7Dは、hChon及びhChon−TGF−β1細胞の混合物(B)又はhChonのみ(D)のいずれかによる注入後の大腿顆の断面におけるメイソン三重染色を示す。[オリジナル倍率:(B及びD)12.5倍]
hChon及びhChon−TGF−β1細胞の混合物を、大腿顆に部分軟骨欠損(3mm×5mm、深さ1〜2mm)を含むウサギ膝関節に注入した。細胞混合物(2×106細胞/mlの15〜20μl、hChonとhChon−TGF−β1との比3:1又は5:1)は、欠損の最上部に供給し、縫合前に細胞が創部に浸透できるように、15〜20分間、欠損内で放置した。試料は、注入の6週間後に回収し、顕微鏡により観察した。図8A及び8Cは、hChon及びhChon−TGF−β1細胞(3:1の比)の混合物(A)又はhChon及びhChon−TGF−β1細胞(5:1の比)の混合物(C)による注入の6週間後の大腿顆の写真を示す。図8B及び8Dは、3:1の比(B)又は5:1の比(D)のhChon及びhChon−TGF−β1細胞の混合物による注入後の大腿顆の断面におけるメイソン三重染色を示す。[オリジナル倍率:(B及びD)12.5倍]
Claims (11)
- a)形質転換成長因子β1(TGF−β1)をコードする遺伝子によりトランスフェクション又は形質導入された線維芽細胞又は軟骨細胞の第一の集団と、
b)TGF−β1をコードする遺伝子によりトランスフェクション又は形質導入されていない軟骨細胞の第二の集団と、
c)その薬学的に許容される担体と、を含み、前記第二の集団と前記第一の集団の混合比が、1〜20対1であることを特徴とする、ヒアリン軟骨生成用混合細胞組成物。 - a)形質転換成長因子β1(TGF−β1)をコードする遺伝子によりトランスフェクション又は形質導入された線維芽細胞又は軟骨細胞の第一の集団と、
b)TGF−β1をコードする遺伝子によりトランスフェクション又は形質導入されていない軟骨細胞の第二の集団と、
c)その薬学的に許容される担体と、を含み、前記第二の集団と前記第一の集団の混合比が、1〜20対1であることを特徴とする、変形関節症ex vivo治療用混合細胞組成物。 - 前記混合細胞組成物は、注入可能であることを特徴とする、請求項1又は2記載の組成物。
- 前記第二の集団と前記第一の集団の混合比は、1〜10対1であることを特徴とする、請求項1記載の組成物。
- 前記第二の集団と前記第一の集団の混合比は、1〜3対1であることを特徴とする、請求項1記載の組成物。
- 前記第一の集団と前記第二の集団とは、同じソースの哺乳類に由来する、請求項1又は2記載の組成物。
- 前記第一の集団と前記第二の集団とは、異なるソースの哺乳類に由来することを特徴とする、請求項1又は2記載の組成物。
- a)プロモータと適切に作用可能に連結した形質転換成長因子β(TGF−β)をコードするDNA配列を含む組み換えベクタを生成するステップと、
b)当該組み換えベクタにより線維芽細胞又は軟骨細胞の集団をin vitroでトランスフェクション又は形質導入するステップと、
c)ヒアリン軟骨生成有効量の(i)TGF−βをコードする遺伝子によりトランスフェクション又は形質導入された線維芽細胞又は軟骨細胞の第一の集団、(ii)TGF−βをコードする遺伝子によりトランスフェクション又は形質導入されていない線維芽細胞又は軟骨細胞の第二の集団、及び(iii)その薬学的に許容される担体、を含む注入可能な混合細胞組成物を、ヒトを除く哺乳類の関節空間内に対して、前記関節空間内でTGF−βをコードするDNA配列の発現が起こり、結果として、前記関節空間内でヒアリン軟骨の生成が生じるように注入するステップと、を含み、前記第二の集団と前記第一の集団の混合比が、3〜20対1であることを特徴とする、ヒトを除く哺乳類においてヒアリン軟骨を生成する方法。 - 前記第二の集団と前記第一の集団の混合比は、3〜10対1である、請求項8記載の方法。
- 前記第二の集団と前記第一の集団の混合比は、10対1である、請求項8記載の方法。
- ヒトを除く哺乳類の変形関節症を治療する方法であって、
a)プロモータと適切に作用可能に連結した形質転換成長因子β(TGF−β)をコードするDNA配列を含む組み換えベクタを生成するステップと、
b)当該組み換えベクタにより線維芽細胞又は軟骨細胞の集団をin vitroでトランスフェクション又は形質導入するステップと、
c)ヒアリン軟骨生成及び変形性関節症治療有効量の
(i)TGF−βをコードする遺伝子によりトランスフェクション又は形質導入された線維芽細胞又は軟骨細胞の第一の集団、
(ii)TGF−βをコードする遺伝子によりトランスフェクション又は形質導入されていない軟骨細胞の第二の集団、及び
(iii)非生物三次元構造ではない薬学的に許容される担体、を含む注入可能な混合細胞組成物を、ヒトを除く哺乳類の関節空間内に対して、前記関節空間内でTGF−βをコードするDNA配列の発現が起こり、結果として、前記関節空間内で骨及び軟骨の生成が生じるように、注入するステップと、を含み、前記第二の集団と前記第一の集団の混合比が、3〜20対1であることを特徴とする、方法。
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- 2003-03-28 DK DK03718103.9T patent/DK1490074T3/en active
- 2003-03-28 WO PCT/US2003/009720 patent/WO2003083080A2/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
KR20050012229A (ko) | 2005-01-31 |
WO2003083080A2 (en) | 2003-10-09 |
DK1490074T3 (en) | 2017-08-14 |
US20100330053A1 (en) | 2010-12-30 |
KR100866101B1 (ko) | 2008-10-30 |
EP1490074A4 (en) | 2006-05-31 |
US20080075703A1 (en) | 2008-03-27 |
US20030185809A1 (en) | 2003-10-02 |
EP1490074A2 (en) | 2004-12-29 |
CN1655798A (zh) | 2005-08-17 |
AU2003222116B2 (en) | 2006-06-15 |
AU2003222116A1 (en) | 2003-10-13 |
US7005127B2 (en) | 2006-02-28 |
CN1307999C (zh) | 2007-04-04 |
US20060115463A1 (en) | 2006-06-01 |
HUE034211T2 (en) | 2018-02-28 |
AU2003222116C1 (en) | 2003-10-13 |
US7282200B2 (en) | 2007-10-16 |
WO2003083080A3 (en) | 2003-12-24 |
CA2480567C (en) | 2012-01-24 |
ES2634500T3 (es) | 2017-09-28 |
JP2009137980A (ja) | 2009-06-25 |
CA2480567A1 (en) | 2003-10-09 |
JP2012236830A (ja) | 2012-12-06 |
EP1490074B1 (en) | 2017-05-10 |
JP2005521732A (ja) | 2005-07-21 |
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