JP4033400B2 - 軟骨細胞とTGF−βを用いた軟骨再生 - Google Patents
軟骨細胞とTGF−βを用いた軟骨再生 Download PDFInfo
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Description
TGF-β cDNA を繊維芽細胞(NIH 3T3-TGF-β1)またはヒト包皮繊維芽細胞/TGF-β1内に形質移入した。それらを10% ウシ胎児血清を含むDulbecco's Modified Eagle's Medium (GIBCO-BRL, Rockville, MD)で培養した。TGF-β1 cDNA 配列を、メタロチオネイン遺伝子プロモーターと共にpmTβ1 ベクター内に追加した。ネオマイシン耐性遺伝子配列もベクター内に挿入した。
総RNAを、イソシアン酸グアニジウム/フェノ−ル/クロロホルムによって細胞から単離した。RNA10 μg を0.66M ホルムアルデヒド含有1.0 % アガロースゲル上で電気泳動し、DURALON-UV 膜に転移させ、UV STRATALINKER (STRATAGENE)でクロスリンクした。ブロットを、1% ウシ血清アルブミン溶液、7% (w/v) SDS、0.5 M リン酸ナトリム、および1 mM EDTA 中65°Cで、予備的にハイブリダイズし、そしてハイブリダイズした。ハイブリダイズしたブロットを、フィルム露出前に、0.1 % SDS、1 X SSC で20分間50°C で洗浄した。RNAブロットを、ヒトTGF-β1に対する32P標識化cDNAプローブでハイブリダイズした。βアクチン用プローブを使用して、サンプル装填の制御を行なった。
試験動物として体重2.0 〜2.5 kg のニュージランド白ウサギを選んだ。ケタミンおよびルンプン(roumpun)で麻酔した後、各ウサギを滅菌した布でおおった。アキレス腱を露出し、104、105、106 個/ml 濃度の細胞0.2 〜 0.3 ml を腱の中間部へ注入した。形質移入したDNAの発現用に、硫酸亜鉛をウサギの飲水に添加した。アキレス腱の実験で至適濃度を決定した後、関節内注入を実施した。膝関節を露出し、ナイフで、部分的および完全に軟骨を欠損させた。肋軟骨を露出させないように注意を払いながら、硝子軟骨層を部分的に欠損させた。すべての硝子軟骨を取り除いた後、完全に欠損させ、肋軟骨を露出させた。手術の創傷を閉じた後、106 個/ml 濃度の細胞を関節内に注入し、硫酸亜鉛を飲水に添加した。
腱と膝関節を収集した後、検体をホルマリンで固定し、硝酸で脱灰した。パラフィンブロックに埋め込み、0.8 μm の厚さにカットした。ヘマトキシリン-エオシンおよびサフラニ-O染色を用いて、顕微鏡下で再生した組織を観察した。
形質移入は、リン酸カルシウムの共沈法によって実施された(図 1)。生存コロニーの約80% が導入遺伝子mRNAを発現した。これらの選択したTGF-β1産生細胞を硫酸亜鉛溶液中でインキュベートした。細胞を100 μM 硫酸亜鉛溶液中で培養すると、mRNAを産生した。TGF-β 分泌速度は、24 時間で細胞106 個につき約32 ngであった。
ウサギのアキレス腱を観察し、NIH 3T3-TGF-β1 細胞の生存能力をチェックした。106 個/ml の細胞濃度における腱は、104や105個/ml 濃度よりも顕著に厚かった。部分的および完全な軟骨欠損を作成した後、106 個/ml 濃度のNIH 3T3-TGF-β1 細胞0.3 ml を膝関節に注入した。注入後2〜6週間後に関節を診察した。部分的欠損軟骨で新たに形成された硝子軟骨が認められた。すなわち、注入2週間後、硝子軟骨が現れ、6週間後に軟骨欠損部は硝子軟骨によって覆われた(図2)。再生された軟骨の厚さは、時間と共に厚くなった(図3)。注入した細胞はTGF-β1を分泌し、それは、TGF-β1 抗体による免疫組織化学染色によって観察することができた(図3)。TGF-β1 の形質移入していない正常な繊維芽細胞を注入した対側は、硝子軟骨で覆われていなかった。部分的損傷領域の再生した硝子軟骨は、サフラニン-O 染色により赤色となった(図4)(新たに形成した軟骨の深さは、損傷部とほぼ同一であった。)。この知見は、注入した細胞が、パラクリン様式の作用によって周辺の正常軟骨細胞を活性化することを示唆している。
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Claims (11)
- TGF- β 1、遺伝子をコード化するベクターを含む可能性のある軟骨細胞若しくは遺伝子をコード化するいかなるベクターも含まない軟骨細胞及び薬剤として利用可能なキャリアを哺乳動物ホストの関節炎の関節スペースに関節内注入させ、その結果、関節スペース中の混合作用によって、結合組織が再生させることを特徴とするTGF-βを活性成分として含む骨関節症の治療剤。
- 軟骨細胞がウイルスベクターを含む、請求項1に記載の治療剤。
- ウイルスベクターがレトロウイルスベクターである、請求項2に記載の治療剤。
- ベクターがプラスミドベクターである、請求項1に記載の治療剤。
- 軟骨細胞が同種異系または自己由来細胞である、請求項1に記載の治療剤。
- TGF- β 1、遺伝子をコード化するベクターを含む可能性のある軟骨細胞若しくは遺伝子をコード化するいかなるベクターも含まない軟骨細胞及び薬剤として利用可能なキャリアを哺乳動物ホストの関節炎の関節スペースに関節内注入させ、その結果、関節スペース中の混合作用によって、結合組織が再生させることを特徴とするTGF-βを活性成分として含む硝子軟骨の再生の治療剤。
- 軟骨細胞がウイルスベクターを含む、請求項6に記載の治療剤。
- ウイルスベクターがレトロウイルスベクターである、請求項7に記載の治療剤。
- ベクターがプラスミドベクターである、請求項6に記載の治療剤。
- 軟骨細胞が同種異系または自己由来細胞である、請求項6に記載の治療剤。
- TGF- β 1、遺伝子をコード化するベクターを含む可能性のある軟骨細胞若しくは遺伝子をコード化するいかなるベクターも含まない軟骨細胞及び薬剤として利用可能なキャリアを哺乳動物ホストの関節炎の関節スペースに関節内注入させ、その結果、関節スペース中の混合作用によって、結合組織が再生させることを特徴とするTGF-βを活性成分として含む関節中の結合組織外傷の治療剤。
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US36376402P | 2002-03-12 | 2002-03-12 | |
PCT/US2003/007486 WO2003077852A2 (en) | 2002-03-12 | 2003-03-12 | CARTILAGE REGENERATION USING CHONDROCYTE AND TGF-β |
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JP7269231B2 (ja) | 2017-06-30 | 2023-05-08 | コーロン ライフ サイエンス インコーポレイテッド | 細胞治療剤の有効性の評価方法 |
SG11202110843WA (en) * | 2019-03-29 | 2021-10-28 | Kolon Tissuegene Inc | CARTILAGE REGENERATION USING CHONDROCYTE AND TGF-ß |
AU2020252087A1 (en) * | 2019-03-29 | 2021-11-18 | Kolon Tissuegene, Inc. | Mixed-cell gene therapy |
CN113372432A (zh) * | 2021-06-15 | 2021-09-10 | 深圳市臻质医疗科技有限公司 | 一种基于化学修饰mRNA编码蛋白因子诱导和/或增强软骨损伤修复的方法 |
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CA2005120A1 (en) * | 1988-12-15 | 1990-06-15 | Anthony F. Purchio | Tgf-beta 1/beta 2: a novel chimeric transforming growth factor-beta |
US5158934A (en) * | 1989-09-01 | 1992-10-27 | Genentech, Inc. | Method of inducing bone growth using TGF-β |
US6413511B1 (en) * | 1990-12-20 | 2002-07-02 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Cartilage alterations by administering to joints chondrocytes comprising a heterologous polynucleotide |
JPH06315992A (ja) * | 1993-05-07 | 1994-11-15 | Ibiden Co Ltd | 発泡スチロ−ル成形体の製造方法 |
IL110589A0 (en) * | 1993-08-10 | 1994-11-11 | Bioph Biotech Entw Pharm Gmbh | Growth/differentiation factor of the TGF- beta family |
US5723331A (en) * | 1994-05-05 | 1998-03-03 | Genzyme Corporation | Methods and compositions for the repair of articular cartilage defects in mammals |
US5902785A (en) * | 1995-06-06 | 1999-05-11 | Genetics Institute, Inc. | Cartilage induction by bone morphogenetic proteins |
US5842477A (en) * | 1996-02-21 | 1998-12-01 | Advanced Tissue Sciences, Inc. | Method for repairing cartilage |
US5700774A (en) * | 1996-03-26 | 1997-12-23 | Genetics Institute, Inc. | Compositions comprising bone morphogenic proteins and truncated parathyroid hormone related peptide, and methods of inducing cartilage by administration of same |
US6315992B1 (en) * | 1999-06-30 | 2001-11-13 | Tissuegene Co. | Generating cartilage in a mammal using fibroblasts transfected with a vector encoding TGF-β-1 |
EP1175228A4 (en) * | 1999-05-03 | 2003-02-26 | Tissuegene Co | GENE THERAPY USING TGF-BETA |
AU6919300A (en) * | 1999-08-20 | 2001-03-19 | University Of Pittsburgh | Methods for in vivo gene delivery to sites of cartilage damage |
KR100394430B1 (ko) * | 1999-12-14 | 2003-08-09 | (주)이노테크 메디칼 | 인간 혈청을 포함하는 인간 세포 배양용 배지 및 이를이용한 인간 세포의 배양 방법 |
AU2002243307A1 (en) * | 2000-11-08 | 2002-07-24 | Tissuegene, Inc. | Gene therapy using tgf-beta |
CA2480554A1 (en) * | 2002-03-28 | 2003-10-09 | Tissuegene, Inc. | Bone generation by gene therapy |
US7005127B2 (en) * | 2002-03-29 | 2006-02-28 | Tissuegene, Inc. | Mixed-cell gene therapy |
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- 2003-03-12 CN CN038105500A patent/CN1653179B/zh not_active Expired - Lifetime
- 2003-03-12 EP EP03721357A patent/EP1485487A4/en not_active Ceased
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EP1485487A4 (en) | 2005-11-09 |
WO2003077852A8 (en) | 2004-12-23 |
JP2005519698A (ja) | 2005-07-07 |
KR100688871B1 (ko) | 2007-03-02 |
KR20050012226A (ko) | 2005-01-31 |
EP1485487A2 (en) | 2004-12-15 |
CA2479042C (en) | 2014-05-13 |
US20030175257A1 (en) | 2003-09-18 |
AU2003224675A1 (en) | 2003-09-29 |
AU2003224675B2 (en) | 2007-05-10 |
CN1653179A (zh) | 2005-08-10 |
CA2479042A1 (en) | 2003-09-25 |
CN1653179B (zh) | 2012-07-25 |
WO2003077852A2 (en) | 2003-09-25 |
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