Gene correction therapy by homologous recombination

• Project/Area Number: 24659265
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Nippon Medical School (2014); 独立行政法人国立精神・神経医療研究センター (2012-2013)
• Principal Investigator: OKADA Takashi 日本医科大学, 医学(系)研究科(研究院), 教授 (00326828)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 遺伝子修正 / 遺伝性神経筋疾患 / 細胞治療 / ゲノム / 細胞 / バイオテクノロジー / DMD / 遺伝子

Outline of Final Research Achievements

Duchenne muscular dystrophy (DMD) is the most common form of childhood muscular dystrophy. Although current gene therapy strategies aim at protein supplementation to recover the function, to correct the mutation in the dystrophin gene must be much-awaited technology as an ultimate goal. Also, since correction by gene editing requires the stable transfer of a functional gene into the target cell, we investigated mesenchymal stromal cells and dental pulp stem cells as platforms of gene and cell therapeutics for the treatment of DMD.

Research Products

• [Journal Article] Intra-Amniotic rAAV-Mediated Microdystrophin Gene Transfer Improves Canine X-Linked Muscular Dystrophy and May Induce Immune Tolerance. (2015)
  • Author(s): Hiromi Hayashita-Kinoh, Naoko Yugeta, Hironori Okada, Yuko Nitahara-Kasahara, Tomoko Chiyo, Takashi Okada and Shin’ichi Takeda
  • Journal Title: Mol. Ther. Volume: 4 Issue: 4 Pages: 627-637
  • DOI: 10.1038/mt.2015.5
  • Peer Reviewed / Open Access
• [Journal Article] Dystrophic mdx mice develop severe cardiac and respiratory dysfunction following genetic ablation of the anti-inflammatory cytokine IL-10. (2015)
  • Author(s): Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Tomoko Chiyo, Akiyo Nishiyama, Hironori Okada, Shin’ichi Takeda and Takashi Okada.
  • Journal Title: Hum Molecular Genetics Volume: 23（15） Issue: 15 Pages: 3990-4000
  • DOI: 10.1093/hmg/ddu113
  • Peer Reviewed / Open Access
• [Journal Article] Cell therapeutic approaches using multipotent mesenchymal stromal cells for muscular dystrophy (2014)
  • Author(s): Yuko Nitahara-Kasahara, Shin’ichi Takeda and Takashi Okada.
  • Journal Title: Inflammation and Regeneration Volume: 34 Issue: 4 Pages: 198-205
  • DOI: 10.2492/inflammregen.34.198
  • NAID: 130004943866
  • ISSN: 1880-8190, 1880-9693
  • Peer Reviewed / Open Access
• [Journal Article] Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration. of its severe phenotype by limited gene expression. (2013)
  • Author(s): Kanagawa M, et. al.
  • Journal Title: Hum Mol Genet Volume: 22 Issue: 15 Pages: 3003-3015
  • DOI: 10.1093/hmg/ddt157
  • Peer Reviewed
• [Journal Article] Initial Pulmonary Respiration Causes Massive Diaphragm Damage and Hyper-CKemia in Duchenne Muscular Dystrophy Dog (2013)
  • Author(s): Nakamura A, Kobayashi M, Kuraoka M, Yuasa K, Yugeta N, Okada T, Takeda S
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 2183-2183
  • DOI: 10.1038/srep02183
  • Peer Reviewed
• [Journal Article] Cell therapeutic approaches using multipotent mesencymal stromal cells for muscular dystrophy (2013)
  • Author(s): Kasahara, Y., Takeda, S., Okada, T.
  • Journal Title: Inflammation and Regeneration Volume: in press
  • Peer Reviewed
• [Journal Article] Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression (2013)
  • Author(s): Motoi Kanagawa
  • Journal Title: Human Molecular Genetics Volume: in press
  • Peer Reviewed
• [Journal Article] Long-term Engraftment of Multipotent Mesenchymal Stromal Cells That Differentiate to Form Myogenic Cells in Dogs With Duchenne Muscular Dystrophy. (2012)
  • Author(s): Yuko Nitahara-Kasahara, et. al.
  • Journal Title: Molecular Therapy Volume: 20 Issue: 1 Pages: 168-177
  • DOI: 10.1038/mt.2011.181
  • Peer Reviewed
• [Presentation] デュシェンヌ型筋ジストロフィー・イヌモデルCXMDJを用いた血清オステオポンチンの解析 (2014)
  • Author(s): 倉岡睦季1、木村円1, 2、永田哲也1、岡田尚巳1,3、今村道博1、武田伸一1, 2
  • Organizer: 第9回筋ジストロフィー治療研究合同発表会
  • Place of Presentation: 箱根
  • Year and Date: 2014-11-01
• [Presentation] Immune tolerance induction of canine X-linked muscular dystrophy with fetal rAAV-microdystrophin transduction. (2014)
  • Author(s): Hiromi Hayashita-Kinoh, Hironori Okada, Yuko Nitahara-Kasahara, Tomoko Chiyo, Naoko Yugeta, Takashi Okada, Shin’ichi Takeda.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Tokyo
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Engraftment of mesenchymeal stem cells is effectively associated by IL-10 in skeletall muscle. (2014)
  • Author(s): Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Nana Tsumita, Tomoko Chiyo, Hironori Okada, Shin’ichi Takeda, Takashi Okada.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Tokyo
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Effective microdystrophin expression in non-human primate muscle with rAAV type 2/8/9 vectors following immune suppression. (2014)
  • Author(s): Akiko Ishii, Hironori Okada, Hiromi Hayashita-Kinoh, Shin Jin-Hong, Takashi Okada, Shin’ichi Takeda.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Tokyo
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] IL10強制発現による機能強化型MSCsの作製と生存解析 (2014)
  • Author(s): 笠原優子, 喜納裕美, 千代智子, 岡田浩典, 武田伸一, 岡田尚巳
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄
  • Year and Date: 2014-07-01 – 2014-07-05
• [Presentation] Immune tolerance induction in Canine X-Linked Muscular Dystrophy with rAAV9-Microdystrophin Transduction. (2014)
  • Author(s): Hiromi Hayashita-Kinoh, Yuko Nitahara-Kasahara, Hironori Okada, Tomoko Chiyo, Naoko Yugeta, Takashi Okada, Shin’ichi Takeda.
  • Organizer: American Society of Gene and Cell Therapy 17th Annual Meeting
  • Place of Presentation: Washington, DC
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Skeletal muscle engraftment of mesenchymal stromal cells is augmented by IL-10. (2014)
  • Author(s): Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Tomoko Chiyo, Hironori Okada, Shin’ichi Takeda, Takashi Okada.
  • Organizer: American Society of Gene and Cell Therapy 17th Annual Meeting
  • Place of Presentation: Washington, DC
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Engraftment of Mesenchymal Stromal Cells That CanDifferentiate To Form Myogenic Cells Is Enhancedby Expressing IL-10 in Dog with Duchenne MuscularDystrophy (2013)
  • Author(s): Nitahara-Kasahara Y, Hayashita-Kinoh H, Chiyo T, Okada H, Okada T, Takeda S
  • Organizer: American society of gene & cell therapy 16th Annual meeting
  • Place of Presentation: Salt Lake City, Utah, USA
• [Presentation] 炎症を伴った筋ジストロフィーモデルマウスの作製と病態解析 (2012)
  • Author(s): 笠原優子
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] IL-10欠損筋ジストロフィーモデルマウスの作製と炎症病態解析 (2012)
  • Author(s): 笠原優子
  • Organizer: 第35回分子生物学会年会
  • Place of Presentation: 福岡
• [Patent(Industrial Property Rights)] 移植用幹細胞及びその製造方法 (2013)
  • Inventor(s): 岡田尚巳、笠原優子、武田伸一
  • Industrial Property Rights Holder: 国立精神･神経医療研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-108408
  • Filing Date: 2013-05-22