ex vivo gene manipulation of mesenchymal stem cell and application to cell therapy

• Project/Area Number: 20200013
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
• Allocation Type: Single-year Grants
• Research Field: Neurology; Neurophysiology and muscle physiology
• Research Institution: Kumamoto University
• Principal Investigator: MAEDA Yasushi 熊本大学, 医学部附属病院, 講師 (60346997)
• Co-Investigator(Kenkyū-buntansha): UCHINO Makoto 熊本大学, 大学院・生命科学研究部, 教授 (20117336) ; KIMURA En 熊本大学, 医学部附属病院, 助教 (60433025)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2010: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2009: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2008: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
• Keywords: 筋ジストロフィー / 細胞治療 / 遺伝子操作 / 間葉系幹細胞 / 移植・再生医療 / 遺伝子 / ウイルスベクター / 骨髄間質細胞

Research Abstract

Bone marrow derived mesenchymal stem cells (MSC) could be isolated and cultured from muscular dystrophy model mouse. And it was proved that gene manipulation by helper-dependent adenovirus of was possible without any tricky technique. Moreover, we found MSC’s novel competence to treat muscular dystrophy. MSC has intrinsic ability to modify muscle degeneration and regeneration. We found various growth factors are produced from MSC, and some growth factors of them give effects on muscle regeneration.

Research Products

• [Journal Article] Rescue From Respiratory Dysfunction by transduction of Full-length Dystrophin to Diaphragm via the Peritoneal Cavity in Utrophn/Dystrophin Double Knockout Mice (2011)
  • Author(s): Ishizaki M, Maeda Y, Kawano R, Suga T, Uchida Y, Uchino K, Yamashita S, Kimura E, Uchino M
  • Journal Title: Molecular Therapy Volume: 19(7) Pages: 1230-5
  • Peer Reviewed
• [Journal Article] Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse (2011)
  • Author(s): Suga T, Kimura E, Morioka Y, Ikawa M, Li S, Uchino K, Uchida Y, Yamashita S, Maeda Y, Chamberlain JS, Uchino M
  • Journal Title: PLoS One. Volume: 6(3)
  • NAID: 120006957404
  • Peer Reviewed
• [Journal Article] Rescue From Respiratory Dysfunction by transduction of Full-length Dystrophin to Diaphragm via the Peritoneal Cavity in Utrophn/Dystrophin Double Knockout Mice (2011)
  • Author(s): Ishizaki M
  • Journal Title: Molecular Therapy Volume: 19 Pages: 1230-35
  • Peer Reviewed
• [Journal Article] Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse (2011)
  • Author(s): Suga T
  • Journal Title: PLoS One Volume: 6
  • Peer Reviewed
• [Journal Article] Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation (2011)
  • Author(s): Mori A
  • Journal Title: Neurochem Int Volume: 58 Pages: 344-53
  • Peer Reviewed
• [Journal Article] A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease (2011)
  • Author(s): Sakaguchi H
  • Journal Title: J Neurol Volume: 258 Pages: 284-90
  • Peer Reviewed
• [Journal Article] Amyotrophic lateral sclerosis in a patient with Kartagener syndrome (2010)
  • Author(s): Yamashita S
  • Journal Title: Amyotroph Lateral Scler Volume: 11 Pages: 402-4
  • Peer Reviewed
• [Journal Article] DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity (2010)
  • Author(s): Yamashita S
  • Journal Title: Journal of Neurochemistry Volume: 113 Pages: 860-70
  • Peer Reviewed
• [Journal Article] DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity (2010)
  • Author(s): Yamashita S
  • Journal Title: Journal of Neurochemistry (In press)
  • Peer Reviewed
• [Journal Article] Dystrophim delivery to muscles of mdx mice using lentiviral vectors leads to myogenic progenitor targeting and stable gene expression (2010)
  • Author(s): Kimura E
  • Journal Title: Molecular Therapy Pages: 206-213
  • Peer Reviewed
• [Journal Article] Transduction of full-length dystrophin to multiple skeletal muscles imp roves motor performance and lifespan in utrophin/dystrophin double kn ockout mice (2008)
  • Author(s): Kawano R
  • Journal Title: Molecular Therapy 16 Pages: 825-831
  • Peer Reviewed
• [Journal Article] Mdx respiratory impairment following fibrosis of the diaphragm (2008)
  • Author(s): Ishizaki M
  • Journal Title: Neuromuscular Disorders 18 Pages: 324-328
  • Peer Reviewed
• [Journal Article] Regions downstream from the WW domain of dystrophin are important for bindine to nostsvnantic densities in the brain (2008)
  • Author(s): Sakamoto T
  • Journal Title: Neuromuscular Disorders 18 Pages: 382-388
  • Peer Reviewed
• [Journal Article] Cell-lineage Regulated Myogenesis for Dystrophin Replacement : a Nov el Therapeutic Annroach for Treatment of Muscular Dvstronhv (2008)
  • Author(s): Kimura E
  • Journal Title: Hum Mol Genet 17 Pages: 2507-17
  • Peer Reviewed
• [Presentation] Repetitive allotransplantation of bone marrow stromal cells to muscular dystrophy model mice drastically improves the body build and life span (2011)
  • Author(s): Maeda Y
  • Organizer: 19th Annual Congress of the European Society of Gene and Cell Therapy(ESGCT)
  • Place of Presentation: Brighton, UK
• [Presentation] DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity (2010)
  • Author(s): Yamashita S
  • Organizer: Society for Neuroscience
  • Place of Presentation: San Diego USA
  • Year and Date: 2010-11-15
• [Presentation] Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse (2010)
  • Author(s): Suga T
  • Organizer: 18^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Milano, Italy
• [Presentation] 幹細胞治療による骨格筋再生と筋ジストロフィーの治療研究 (2010)
  • Author(s): 内野 克尚
  • Organizer: 第28 回日本神経治療学会総会
  • Place of Presentation: 横浜(パシフィコ横浜)
• [Presentation] Lentiviral vector mediated delivery of full-length dystrophin for gene therapy of muscular dystrophy (2010)
  • Author(s): 木村 円
  • Organizer: 第16回日本遺伝子治療学会年次学術集会
  • Place of Presentation: 宇都宮(栃木県総合文化センター)
• [Presentation] Transduction of full-length dystrophin to diaphragm ameliorates respiratory dysfunction in severe dystrophic mouse (2010)
  • Author(s): Ishizaki M
  • Organizer: 13^<th> Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC, USA
• [Presentation] Lentiviral vector mediated delivery of full-length dystrophin for gene therapy of muscular dystrophy (2010)
  • Author(s): Kimura E
  • Organizer: 3^<th> Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC USA
• [Presentation] Lentiviral vector を用いたDuchenne 型筋ジストロフィー遺伝子治療研究 (2010)
  • Author(s): 菅 智宏
  • Organizer: 第51 回日本神経学会総会
  • Place of Presentation: 東京(東京国際フォーラム)
• [Presentation] Lentiviral vector mediated delivery of full-length dystrophin for gene therapy of muscular dystrophy (2010)
  • Author(s): Kimura E
  • Organizer: 13^<th> Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC USA
• [Presentation] Transduction of full-length dystrophin to diaphragm ameliorates respiratory dysfunction in severe dystrophic mouse (2010)
  • Author(s): Ishizaki M
  • Organizer: 13^<th> Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC USA
• [Presentation] Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse (2010)
  • Author(s): Suga T
  • Organizer: 18^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Milano Italy
• [Presentation] Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation (2010)
  • Author(s): Mori A
  • Organizer: Neuroscience 2010
  • Place of Presentation: San Diego USA
• [Presentation] Lentiviral vector mediated delivery of full-length dystrophin for gene Therapy of muscular dystrophy (2010)
  • Author(s): 木村円
  • Organizer: 第16回日本遺伝子治療学会年次学術集会
  • Place of Presentation: 栃木県総合文化センター(宇都宮)
• [Presentation] DJ-1は変異SOD1と相互作用し、神経毒性を軽減する (2010)
  • Author(s): 山下賢
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京)
• [Presentation] Lentiviral vectorを用いたDuchenne型筋ジストロフィー遺伝子治療研究 (2010)
  • Author(s): 菅智宏
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京)
• [Presentation] 幹細胞治療による骨格筋再生と筋ジストロフィーの治療研究 (2010)
  • Author(s): 内野克尚
  • Organizer: 第28回日本神経治療学会総会
  • Place of Presentation: パシフィコ横浜(横浜)
• [Presentation] Transduction of full-length dystrophin to diaphragm ameliorates respiratory dysfunction in severe dystrophic mouse (2009)
  • Author(s): Ishizaki M
  • Organizer: 17th Annual Congress of the European Society of Gene and Cell Therapy(ESGCT)
  • Place of Presentation: Hannover, Germany, Convention Center at Hannover Fairground
• [Presentation] Full-dystrophin packaging in lentiviral vector for a gene therapy of Duchenne muscular dystrophy (2009)
  • Author(s): Kimura E
  • Organizer: 17th Annual Congress of the European Society of Gene and Cell Therapy(ESGCT)
  • Place of Presentation: Hannover, Germany, Convention Center at Hannover Fairground
• [Presentation] 横隔膜へのジストロフィン導入による筋ジストロフィーモデルマウスの呼吸機能改善効果 (2009)
  • Author(s): 前田 寧
  • Organizer: 第50 回日本神経学会総会
  • Place of Presentation: 仙台国際センター
• [Presentation] 筋ジストロフィー根本治療に向けての骨髄間質間葉系幹細胞へのウイルスベクターによる遺伝子操作 (2009)
  • Author(s): 前田 寧
  • Organizer: 第27 回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] Lentiviral vector を用いたDuchenne 型筋ジストロフィー遺伝子治療研究 (2009)
  • Author(s): 菅 智宏
  • Organizer: 第27 回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] 幹細胞治療による骨格筋再生と筋ジストロフィーの治療研究 (2009)
  • Author(s): 木村 円
  • Organizer: 第27回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] 骨格筋幹細胞をターゲットとしたDuchenne muscular dystrophy の治療研究 (2009)
  • Author(s): 木村 円
  • Organizer: 第50 回日本神経学会総会
  • Place of Presentation: 仙台国際センター
• [Presentation] Transduction of full-length dystrophin to diaphragm diaphragm ameliorates respiratory dysfunction in severe dystrophic mouse (2009)
  • Author(s): Ishizai M
  • Organizer: 17th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT)
  • Place of Presentation: Hannover, Germany, Convention Center at Hannover Fairground
• [Presentation] Full-dystrophin packaging in lentiviral vector for a genetherapy of Duchenne muscular dystrophy (2009)
  • Author(s): Kimura E
  • Organizer: 17th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT)
  • Place of Presentation: Hannover, Germany, Convention Center at Hannover Fairground
• [Presentation] 横隔膜へのジストロフィン導入による筋ジストロフィーモデルマウスの呼吸機能改善効果 (2009)
  • Author(s): 前田寧
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台国際センター
• [Presentation] 筋ジストロフィー根本治療に向けての骨髄間質間葉系幹細胞へのウイルスベクターによる遺伝子操作 (2009)
  • Author(s): 前田寧
  • Organizer: 第27回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] 筋ジストロフィーモデルマアスの呼吸機能解析及びと横隔膜への完全長dystrophin導入による呼吸機能改善 (2009)
  • Author(s): 石崎雅俊
  • Organizer: 第27回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] Lentiviral vectorを用いたDuchenne型筋ジストロフィー遺伝子治療研究 (2009)
  • Author(s): 菅智宏
  • Organizer: 第27回日本神経治療学会総会
  • Place of Presentation: 熊本市民会館
• [Presentation] 骨格筋幹細胞をターゲットとしたDuchenne muscular dystrophyの治療研究 (2009)
  • Author(s): 木村円
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台国際センター
• [Presentation] DJ-1による変異SOD1毒性の軽滅効果に関する検討 (2009)
  • Author(s): 山下賢
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台国際センター
• [Presentation] Gene therapy ta dystrophic diaphragm by the helper dependent adenovirus vector(HDAdv)-mediated full-length dystrophin expression (2008)
  • Author(s): Ishizaki M
  • Organizer: American Society of Gene Therapy 11^<th> annual meeting
  • Place of Presentation: Boston,USA JohnB. Hynes Convention Center
  • Year and Date: 2008-05-28
• [Presentation] Mdx diaphragm muscle as a target of dystrophin gene therapy (2008)
  • Author(s): Suga T
  • Organizer: Annual Congress of the European Society of Gene and Cell therapy
  • Place of Presentation: Brugge, Belgium Concert gebouw Brugge
• [Presentation] Lentiviral vectorを用いたDuchenne muscular dystrophyの治療研究 (2008)
  • Author(s): 木村円
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 薪世代アデノウイルスベクターを用いた横隔膜へのdystrophin導入 (2008)
  • Author(s): 石崎雅俊
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 筋ジストロフィーモデルマウスの骨格筋への完全長dystrophin導入の効果 (2008)
  • Author(s): 前田寧
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 中枢神経におけるdystrophinの局在に関する検討 (2008)
  • Author(s): 阪本徹郎
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 骨格筋幹細胞をターゲットにした筋ジストロフィー遺伝子治療研究 (2008)
  • Author(s): 木村円
  • Organizer: 第26回日本神経治療学会
  • Place of Presentation: 新横浜プリンスホテル
• [Presentation] 骨格筋幹細胞をターゲットとしたdystrophin遺伝子導入 (2008)
  • Author(s): 菅智宏
  • Organizer: 第26回日本神経治療学会
  • Place of Presentation: 新横浜プリンスホテル