JP4451135B2 - 生体接着指向体細胞療法 - Google Patents
生体接着指向体細胞療法 Download PDFInfo
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- JP4451135B2 JP4451135B2 JP2003579839A JP2003579839A JP4451135B2 JP 4451135 B2 JP4451135 B2 JP 4451135B2 JP 2003579839 A JP2003579839 A JP 2003579839A JP 2003579839 A JP2003579839 A JP 2003579839A JP 4451135 B2 JP4451135 B2 JP 4451135B2
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- tgf
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- bmp
- cartilage
- chondrocytes
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Description
リン酸カルシウム共沈法を使ってトランスフェクションを実施した(図1A〜1C)。生存コロニーの約80%がトランスジーン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培養した。細胞を100mM硫酸亜鉛中で培養した場合、該細胞はmRNAを産生した。TGF-β分泌率は、約32ng/106個細胞/24時間であった。
部分および完全軟骨欠損を作り出した後、0.3mlのNIH3T3-TGF-β1細胞106個/mlを膝関節に注入した。注入から2〜6週間後に関節を調べた。部分損傷軟骨では、新たに形成されたヒアリン軟骨が認められた。注入から2週間後、ヒアリン軟骨が現われ、注入から6週間後、軟骨欠損部がヒアリン軟骨で覆われた(図2)。再生した軟骨は、経時的に厚さが厚くなった(図3)。注入細胞はTGF-β1を分泌し、それは、TGF-β1抗体による免疫組織化学的染色によって認めることができた(図3)。TGF-β1トランスフェクションなしの正常線維芽細胞を注入した反対側は、ヒアリン軟骨で覆われなかった。部分損傷領域では、再生ヒアリン軟骨は、サフラニン−O染色で赤色に着色した(図4)。新たに形成された軟骨の深さは、欠損の深さとほぼ同一であった。この所見は、注入した細胞がパラクリン作用形態によって周囲の正常軟骨を活性化することを示唆している。
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試験に選択した。これらのウサギは成熟しており、タイドマークを有した。膝関節を露出し、部分軟骨欠損(3mm x 6mm、深さ1〜2mm)又は全層軟骨欠損(3mm x 6mm、深さ2〜3mm)を、大腿骨顆のヒアリン軟骨層に外科用メスで作り出した。対照ヒト軟骨細胞(hChon)、hChonおよびNIH3T3-TGF-β1細胞の混合物、またはNIH3T3-BMP-2細胞を、欠損のあるウサギの膝関節に注入した。これらの細胞(細胞2 x 106個/mlを15〜20μl)を欠損部の最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。hChonおよびNIH3T3-BMP-2細胞の混合物による実験では、欠損部作製から3週間後にこれらの細胞を欠損部に注入した。細胞注入から6週間または12週間後に大腿骨顆を採取して調べた。
対照hChon、またはhChonおよびNIH3T3-TGF-β1細胞の混合物を、大腿骨顆に部分軟骨欠損(3mm x 5mm、深さ1〜2mm)を持つウサギの膝関節に注入した。細胞混合物(細胞2 x 106個/mlを15〜20μl、hChon対NIH3T3-TGF-β1細胞比が10:1)を欠損部最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。注入から6週間後に検体を採取し、顕微鏡で観察した。図11AおよびCは、hChonおよびNIH3T3-TGF-β1細胞の混合物(A)またはhChon単独(C)の注入から6週間後の大腿骨顆図を示す。図11BおよびDは、hChonおよびNIH3T3-TGF-β1細胞の混合物(B)またはhChon単独(D)を注入した大腿骨顆の切片のマッソン三重染色を示す。[元の倍率:(BおよびD) x 12.5]
対照hChon、またはhChonおよびNIH3T3-TGF-β1細胞の混合物を、大腿骨顆に全層軟骨欠損(3mm x 5mm、深さ2〜3mm)を呈したウサギの膝関節に注入した。細胞混合物(細胞2 x 106個/mlを20〜25μl、hChon対NIH3T3-TGF-β1細胞比が10:1)を欠損部最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。注入から12週間後に検体を採取し、顕微鏡で観察した。図12AおよびDは、hChonおよびNIH3T3-TGF-β1細胞の混合物(A)またはhChon単独(D)の注入から12週間後の大腿骨顆図を示す。図12B、CおよびEは、hChonおよびNIH3T3-TGF-β1細胞の混合物(BおよびC)またはhChon単独(E)を注入した大腿骨顆の切片のマッソン三重染色(BおよびE)およびサフラニン-O染色(C)を示す。[元の倍率:(B、CおよびE) x 12.5]
対照hChon、またはhChonおよびNIH3T3-BMP-2細胞の混合物を、大腿骨顆に部分軟骨欠損(3mm x 5mm、深さ1〜2mm)を持つウサギの膝関節に注入した。細胞混合物(細胞2 x 106個/mlを15〜20μl、hChon対NIH3T3-BMP-2細胞比が10:1)を欠損部最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。注入から6週間後に検体を採取し、顕微鏡で観察した。図13AおよびCは、hChonおよびNIH3T3-BMP-2細胞の混合物(A)またはhChon単独(C)の注入から6週間後の大腿骨顆図を示す。図13BおよびDは、hChonおよびNIH3T3- BMP-2細胞の混合物(B)またはhChon単独(D)を注入した大腿骨顆の切片のマッソン三重染色を示す。[元の倍率:(BおよびD) x 12.5]
対照hChon、またはhChonおよびNIH3T3-BMP-2細胞の混合物を、大腿骨顆に全層軟骨欠損(3mm x 5mm、深さ2〜3mm)を持つウサギの膝関節に注入した。この場合、細胞は、欠損作製から3週間後に注入した。細胞混合物(細胞2 x 106個/mlを20〜25μl、hChon対NIH3T3-BMP-2細胞比が10:1)を欠損部最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。注入から6週間後に検体を採取し、顕微鏡で観察した。図14AおよびDは、hChonおよびNIH3T3-BMP-2細胞の混合物(A)またはhChon単独(D)の注入から12週間後の大腿骨顆図を示す。図14B、CおよびEは、hChonおよびNIH3T3-BMP-2細胞の混合物(BおよびC)またはhChon単独(E)を注入した大腿骨顆の切片のマッソン三重染色(BおよびE)とサフラニン-O染色(C)を示す。[元の倍率:(B、CおよびE) x 12.5]
対照ヒト軟骨細胞(hChon)、またはhChonおよびhChon-TGF-β1細胞の混合物を、大腿骨顆に全層軟骨欠損(3mm x 5mm、深さ2〜3mm)を持つウサギの膝関節に注入した。細胞混合物(細胞2 x 106個/mlを20〜25μl、hChon対hChon-TGF-β1細胞比が1:1)を欠損部最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に細胞を創傷部に浸透させた。注入から6週間後に検体を採取し、顕微鏡で観察した。図15Aおよび15Cは、hChonおよびhChon-TGF-β1細胞の混合物(A)またはhChon単独(C)の注入から6週間後の大腿骨顆図を示す。図15Bおよび15Dは、hChonおよびhChon-TGF-β1細胞の混合物(B)またはhChon単独(D)を注入した大腿骨顆の切片のマッソン三重染色を示す。[元の倍率:(BおよびD) x 12.5]
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試験に選択した。これらのウサギは成熟しており、タイドマークを有した。膝関節を露出し、部分軟骨欠損(3mm x 6mm、深さ1〜2mm)を、大腿骨顆のヒアリン軟骨層に手術用メスで作り出した。対照ウサギバフィーコート(rBC)、またはウサギバフィーコートおよびTGF-β1産生細胞(NIH3T3-TGF-β1細胞、細胞2 x 106個/mlを15〜20μl)の混合物を欠損部に負荷した後、欠損部に15〜20分間放置し、縫合前に該混合物を創傷部に浸透させた。注入から6週間または8週間後に大腿骨顆を採取した。
hChonおよびhChon-TGF‐β1細胞の混合物を、大腿骨顆の部分軟骨欠損または全層軟骨欠損(3mm x 5mm、深さ1〜2mmまたは2〜3mm)を含むウサギの膝関節に注入した。細胞混合物(細胞2 x 106個/mlを10〜15μlまたは20〜25μl、1:100希釈GPによるhChon対hChon-TGF-β1比が1:1)を欠損部の最上端に負荷した後、欠損部に15〜20分間放置し、縫合前に該細胞を創傷部に浸透させた。注入後6週間目に検体を採取し、顕微鏡で観察した。図17Aおよび17Cは、部分(A)または全層欠損部(C)での、hChonおよびhChon-TGF‐β1細胞の混合物の注入から6週間後の大腿骨顆図を示す。図17Bおよび17Dは、部分(B)または全層欠損部(D)にhChonおよびhChon-TGF‐β1細胞の混合物を注入した大腿骨顆の切片のマッソン三重染色を示す。[元の倍率:(BおよびD)x 12.5]
Claims (16)
- 治療有効量の、トランスフォーミング成長因子β(TGF−β)スーパーファミリーに属するサイトカインをコード化する治療遺伝子でトランスフェクトまたは形質導入した線維芽細胞または軟骨細胞と、接着有効量の精製されたバフィーコートを含むヒアリン軟骨生成用または骨関節炎治療用組成物。
- 前記治療遺伝子が、トランスフォーミング成長因子β(TGF−β)または骨形成因子(BMP)であることを特徴とする請求項1に記載の組成物。
- 前記線維芽細胞または軟骨細胞をTGF−β1またはBMP−2でトランスフェクトまたは形質導入することを特徴とする請求項1に記載の組成物。
- バフィーコート対細胞の量比が体積換算で1〜5対1であることを特徴とする請求項1に記載の組成物。
- 前記細胞に放射線照射することを特徴とする請求項1に記載の組成物。
- 前記細胞をいずれかのDNAでトランスフェクトまたは形質導入していない細胞と混合することを特徴とする請求項1に記載の組成物。
- ヒトを除く哺乳類の標的部位で遺伝子発現を限局させる方法で、接着有効量の精製されたバフィーコートをTGF−βスーパーファミリーに属するサイトカインをコード化する治療遺伝子を含む組換えベクターでトランスフェクトまたは形質導入された線維芽細胞または軟骨細胞と混合し、ヒアリン軟骨生成用または骨関節炎治療用組成物を形成し、該組成物を関節腔に投与することを含む方法。
- 前記治療遺伝子がトランスフォーミング成長因子β(TGF−β)または骨形成タンパク(BMP)であることを特徴とする請求項7に記載の方法。
- 前記細胞を放射線照射することを特徴とする請求項7に記載の方法。
- 前記組成物が、さらにTGF−βスーパーファミリーに属するサイトカインをコード化する治療遺伝子を含む組換えベクターでトランスフェクトまたは形質導入していない細胞を含むことを特徴とする請求項7に記載の方法。
- 前記細胞を移植前に保存することを特徴とする請求項7に記載の方法。
- 前記トランスフェクションまたは形質導入を、リポソームカプセル化、リン酸カルシウム共沈、電気穿孔法、DEAE−デキストラン介在法またはウイルス介在法で実現することを特徴とする請求項7に記載の方法。
- 哺乳類にヒアリン軟骨を生成する方法であり、
a)トランスフォーミング成長因子β(TGF−β)または骨形成因子(BMP)をコード化するDNA配列を含む組換えベクターを生成し、
b)試験管内で前記組換えベクターで線維芽または軟骨細胞群をトランスフェクトまたは形質導入し、
c)TGF−βまたはBMPをコード化するDNA配列の関節腔内での発現が起こり、関節腔内でヒアリン軟骨が生成するように、ヒアリン軟骨の生成に有効な量の(i)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導した繊維芽または軟骨細胞群、(ii)接着性に有効な量の精製されたバフィーコート、(iii)薬学的に許容可能なそのキャリア、
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腔に注入することを含むヒアリン軟骨生成方法。 - 哺乳類にヒアリン軟骨を生成する方法であり、
a)トランスフォーミング成長因子β(TGF−β)または骨形成因子(BMP)をコード化するDNA配列を含む組換えベクターを生成し、
b)試験管内で前記組換えベクターで線維芽または軟骨細胞群をトランスフェクトまたは形質導入し、
c)TGF−βまたはBMPをコード化するDNA配列の関節腔内での発現が起こり、関節腔内でヒアリン軟骨が生成するように、ヒアリン軟骨の生成に有効な量の(i)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導した繊維芽または軟骨細胞群、(ii)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導していない繊維芽または軟骨細胞群、(iii)接着性に有効な量の精製されたバフィーコート、(iv)薬学的に許容可能なそのキャリア、
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腔に注入することを含むヒアリン軟骨生成方法。 - 骨関節炎を治療する方法であり、
a)トランスフォーミング成長因子β(TGF−β)または骨形成因子(BMP)をコード化するDNA配列を含む組換えベクターを生成し、
b)試験管内で前記組換えベクターで線維芽または軟骨細胞群をトランスフェクトまたは形質導入し、
c)TGF−βまたはBMPをコード化するDNA配列の関節腔内での発現が起こり、関節腔内で骨および軟骨が生成するように、骨生成および軟骨生成に有効な量の(i)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導した繊維芽または軟骨細胞群、(ii)接着性に有効な量の精製されたバフィーコート、(iii)薬学的に許容可能なそのキャリア、
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腔に注入することを含む骨関節炎治療法。 - 骨関節炎を治療する方法であり、
a)トランスフォーミング成長因子β(TGF−β)または骨形成因子(BMP)をコード化するDNA配列を含む組換えベクターを生成し、
b)試験管内で前記組換えベクターで線維芽または軟骨細胞群をトランスフェクトまたは形質導入し、
c)TGF−βまたはBMPをコード化するDNA配列の関節腔内での発現が起こり、関節腔内で骨および軟骨の生成が生成するように、骨生成および軟骨生成に有効な量の(i)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導した線維芽または軟骨細胞群、(ii)TGF−βまたはBMPをコード化する遺伝子でトランスフェクトまたは形質誘導していない線維芽または軟骨細胞群、(iii)接着性に有効な量の精製されたバフィーコート、(iv)薬学的に許容可能なそのキャリア、
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腔に注入することを含む骨関節炎を治療する方法。
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US36911102P | 2002-03-29 | 2002-03-29 | |
PCT/US2003/009719 WO2003082302A2 (en) | 2002-03-29 | 2003-03-28 | Bioadhesive directed somatic cell therapy |
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EP (1) | EP1490075A4 (ja) |
JP (1) | JP4451135B2 (ja) |
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US7005127B2 (en) | 2002-03-29 | 2006-02-28 | Tissuegene, Inc. | Mixed-cell gene therapy |
WO2004070042A1 (en) * | 2003-02-10 | 2004-08-19 | Max-Delbrück-Centrum Für Molekulare Medizin (Mdc) | Transposon-based targeting system |
BE1015610A3 (nl) * | 2003-07-17 | 2005-06-07 | Corrutech Nv | Verbeterde lijm en werkwijze voor het vervaardigen ervan. |
US7897384B2 (en) | 2003-09-08 | 2011-03-01 | Ethicon, Inc. | Chondrocyte therapeutic delivery system |
US7927599B2 (en) | 2003-09-08 | 2011-04-19 | Ethicon, Inc. | Chondrocyte therapeutic delivery system |
US8697139B2 (en) | 2004-09-21 | 2014-04-15 | Frank M. Phillips | Method of intervertebral disc treatment using articular chondrocyte cells |
CA2599589A1 (en) * | 2005-02-07 | 2006-08-17 | Genenews,Inc. | Mild osteoarthritis biomarkers and uses thereof |
KR20080038310A (ko) * | 2005-06-23 | 2008-05-06 | 티슈진, 인코포레이티드 | 신경보호 효과 화합물 |
US20140255364A1 (en) * | 2011-10-28 | 2014-09-11 | Tufts University | 3d culture system for culturing cells in synovial fluid, cells cultured in synovial fluid and their use |
AU2018290629B2 (en) | 2017-06-30 | 2022-07-07 | Kolon Life Science, Inc. | Method for assessing validity of cell therapy product |
EP3646878A4 (en) * | 2017-06-30 | 2021-03-24 | Kolon Life Science, Inc. | PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OR TREATMENT OF OSTEOARTHRITIS |
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US4806523A (en) * | 1985-08-06 | 1989-02-21 | Collagen Corporation | Method of treating inflammation |
US5266480A (en) * | 1986-04-18 | 1993-11-30 | Advanced Tissue Sciences, Inc. | Three-dimensional skin culture system |
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 |
US5858355A (en) | 1990-12-20 | 1999-01-12 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | IRAP gene as treatment for arthritis |
CA2155929A1 (en) | 1993-12-14 | 1995-06-22 | Christopher H. Evans | Systemic gene treatment of connective tissue diseases |
US5965125A (en) * | 1995-10-25 | 1999-10-12 | Transkaryotic Therapies, Inc. | Hybrid matrix implants and explants |
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 |
US6151525A (en) | 1997-11-07 | 2000-11-21 | Medtronic, Inc. | Method and system for myocardial identifier repair |
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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 |
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US7431922B2 (en) | 2008-10-07 |
EP1490075A4 (en) | 2008-07-30 |
CN1655802B (zh) | 2011-02-23 |
JP2005537222A (ja) | 2005-12-08 |
CA2480656A1 (en) | 2003-10-09 |
WO2003082302A9 (en) | 2005-01-20 |
KR20050002898A (ko) | 2005-01-10 |
KR100572217B1 (ko) | 2006-04-24 |
WO2003082302A2 (en) | 2003-10-09 |
WO2003082302A3 (en) | 2003-12-18 |
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AU2003218464B2 (en) | 2006-09-21 |
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