Cell therapeutic approach using gene-transduced mesenchymal stromal cells for muscular dystrophy

• Project/Area Number: 26860273
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Nippon Medical School (2016); National Center of Neurology and Psychiatry (2014-2015)
• Principal Investigator: YUKO KASAHARA 日本医科大学, 大学院医学研究科, 助教 (90391911)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 間葉系幹細胞 / 筋ジストロフィー / 骨髄幹質細胞 / 細胞移植 / IL-10 / 抗炎症療作用 / 骨髄間葉系幹細胞 / 疾患モデル動物 / 炎症 / 抗炎症性サイトカイン

Outline of Final Research Achievements

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory and cardiac failure. Inflammation is involved in the pathogenesis of muscular dystrophy and therefore immunosuppressants can be utilized to improve muscle function. For cell therapeutic approach, multipotent mesenchymal stromal cells (MSCs) are promising because of their immunosuppressive properties and ability to differentiate into myogenic-lineage. In this study, we demonstrated that the correlations of inflammation with the severity of DMD by the results of dystrophic mice, which exhibited more severe inflammation and cardiorespiratory dysfunction by genetic ablation of IL-10. We established safe and effective cell transplantation of MSCs into DMD dogs and also indicated the effects of IL-10 on the MSCs engraftment in the skeletal muscle. The strategy would be promising for the anti-inflammatory therapy of DMD, although further study is required for the mechanism of interaction.

Research Products

• [Journal Article] Low intensity training and the C5a complement antagonist NOX-D21 rescue the mdx phenotype through modulation of inflammation. (2017)
  • Author(s): Janek Hyzewicz, Jun Tanihata, Mutsuki Kuraoka, Yuko Nitahara-Kasahara, Teiva Beylier, Urs T Ruegg, Axel Vater, Shin’ichi Takeda.
  • Journal Title: American Journal of Pathology Volume: 187 Issue: 5 Pages: 1147-1161
  • DOI: 10.1016/j.ajpath.2016.12.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory predisposition predicts disease phenotypes in muscular dystrophy. (2016)
  • Author(s): Yuko Nitahara-Kasahara, Shin’ichi Takeda and Takashi Okada.
  • Journal Title: Inflammation and Regeneration Volume: 36 Issue: 1 Pages: 1-5
  • DOI: 10.1186/s41232-016-0019-0
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector. (2016)
  • Author(s): Nakamura-Takahashi A, Miyake K, Watanabe A, Hirai Y, Iijima O, Miyake N, Adachi K, Nitahara-Kasahara Y, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millán JL, Shimada T, Okada T.
  • Journal Title: Mol Ther Methods Clin Dev. Volume: 3 Pages: 15059-15059
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intra-amniotic rAAV-mediated microdystrophin gene transfer improves canine X-linked muscular dystrophy and may induce immune tolerance. (2015)
  • Author(s): Hayashita-Kinoh H, Yugeta N, Okada H, Nitahara-Kasahara Y, Chiyo T, Okada T, Takeda S
  • Journal Title: Mol Ther. Volume: 4 Pages: 627-627
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] 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] Cell therapeutic approaches using multipotent mesencymal stromal cells for muscular dystrophy. (2014)
  • Author(s): Yuko Nitahara-Kasahara, Shin’ichi Takeda and Takashi Okada.
  • Journal Title: Inflammation and Regeneration Volume: 34 Pages: 198-205
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction (2014)
  • Author(s): Sumimasa Arimura, Takashi Okada, Tohru Tezuka, Tomoko Chiyo, Yuko Kasahara, Toshiro Yoshimura, Masakatsu Motomura, Nobuaki Yoshida, David Beeson, Shin’ichi Takeda, Yuji Yamanashi
  • Journal Title: Science Volume: 345 Issue: 6203 Pages: 1505-1508
  • DOI: 10.1126/science.1250744
  • Peer Reviewed / Open Access
• [Presentation] 歯髄幹細胞を用いた筋ジストロフィーに対する細胞治療 (2017)
  • Author(s): 笠原 優子、倉岡 睦季、喜納 裕美、島津 苑子、増田 千明、高橋 有希、今川 究、平戸 徹、武田 伸一、岡田 尚巳
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-07
• [Presentation] Cell therapeutic approach using dental pulp stromal cells for Duchenne muscular dystrophy. (2016)
  • Author(s): Yuko Nitahara-Kasahara, Mutsuki Kuraoka, Hiromi HayashitaKinoh, Aki Takahashi, Chiaki Masuda, Kiwamu Imagawa, Katsuhiko Tachibana, Shin'ichi Takeda and Takashi Okada.
  • Organizer: 22nd Annual Meeting of Japan Society of Gene & Cell Therapy
  • Place of Presentation: 東京
  • Year and Date: 2016-07-28
• [Presentation] Exacerbation in the IL-10 deficient dystrophic mice and an anti-inflammatory strategy with mesenchymal stromal cells. (2016)
  • Author(s): Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Nana Tsumita, Hironori Okada, Shin'ichi Takeda and Takashi Okada.
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] IL-10欠損mdxマウスによって示された炎症素因による筋ジストロフィー組織 (2015)
  • Author(s): 笠原 優子，喜納 裕美，積田 奈々，武田 伸一，岡田 尚巳.
  • Organizer: 第１回日本筋学会
  • Place of Presentation: Tokyo
  • Year and Date: 2015-08-08
• [Presentation] Mesenchymal stromal cells ameliorate progressive phenotype of Duchenne muscular dystrophy in dog. (2015)
  • Author(s): Kasahara Y, Kinoh H, Kuraoka M, Chiyo T, Okada H, Tsumita N, Imagawa K, Tachibana K, Takeda S, Okada T.
  • Organizer: 22th Annual Meeting of Japan Society of Gene & Cell Therapy
  • Place of Presentation: Osaka
  • Year and Date: 2015-07-24
• [Presentation] Improved transduction of canine X-linked muscular dystrophy with rAAV9- microdystrophin by MSCs pretreatment. (2015)
  • Author(s): Hayashita-Kinoh H, Nitahara-Kasahara Y, Okada H, Chiyo T, Imagawa K, Tachibana K, Takeda S, Okada T.
  • Organizer: The 21st Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: Osaka
  • Year and Date: 2015-07-24
• [Presentation] Ultrasound-mediated transient modulation of blood-brain interface in adult common marmoset to induce brain pathology with rAAV. (2015)
  • Author(s): Okada H, Ishibashi H, Masuda C, Hayashita-Kinoh H, Chiyo T, Nitahara-Kasahara Y, Endo- Takahashi Y, Kato K, Negishi Y, Takeda S, Okada T.
  • Organizer: The 21st Annual Meeting of Japan Society of Gene Therapy.
  • Place of Presentation: Osaka
  • Year and Date: 2015-07-24
• [Presentation] 炎症素因による筋ジストロフィー組織障害の重症化 (2015)
  • Author(s): 笠原 優子，喜納 裕美，積田 奈々，武田 伸一，岡田 尚巳.
  • Organizer: 第３６回日本炎症・再生医学会
  • Place of Presentation: Tokyo
  • Year and Date: 2015-07-21
• [Presentation] Mesenchymal Stromal Cells Can Ameliorate the Progressive Phenotype of Dog With Duchenne Muscular Dystrophy. (2015)
  • Author(s): Nitahara-Kasahara Y, Hayashita-Kinoh H, Kuraoka M, Chiyo T, Okada H, Tsumita N, Imagawa K, Tachibana K, Takeda S, Okada T.
  • Organizer: 18th Annual Meeting of American Society of Gene & Cell Therapy
  • Place of Presentation: New Orleans, U.S.A.
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Blood-Brain Interface Opening By Ultrasound in Adult Common Marmoset To Induce Brain Pathology With rAAV. (2015)
  • Author(s): Okada H, Ishibashi H, Masuda C, Hayashita-Kinoh H, Chiyo T, Nitahara-Kasahara Y, Endo-Takahashi Y, Kato K, Negishi Y, Takeda S, Okada T.
  • Organizer: American society of gene & cell therapy 18th Annual meeting.
  • Place of Presentation: New Orleans, U.S.A.
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Improved Transduction of Canine X-Linked Muscular Dystrophy With rAAV9-Microdystrophin By Using MSCs Pretreatment. (2015)
  • Author(s): Hayashita-Kinoh H, Okada H, Nitahara-Kasahara Y, Chiyo T, Imagawa K, Tachibana K, Takeda S, Okada T.
  • Organizer: American society of gene & cell therapy 18th Annual meeting.
  • Place of Presentation: New Orleans, U.S.A.
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Engraftment of mesenchymal stromal cells is effectively associated by IL-10 in skeletal muscle (2014)
  • Author(s): Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Nana Tsumita, Tomoko Chiyo, Hironori Okada, Shin'ichi Takeda and Takashi Okada
  • Organizer: Japan Society of Gene & Cell Therapy 20th Annual Meeting
  • Place of Presentation: 東京慈恵会医科大学、東京都港区
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] IL-10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: 万国津梁館、沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-04
• [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 & Cell Therapy 17th Annual Meeting
  • Place of Presentation: the Marriott Wardman Park Hotel, Wahington DC, USA
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Immune Tolerance Induction in Canine X-Linked Muscular Dystrophy With rAAV9-Microdystrophin Transduction. (2014)
  • Author(s): Hiromi Hayashita-Kinoh, Yuko Nitahara-Kasahara, Tomoko Chiyo, Takashi Okada,Shin’ichi Takeda.
  • Organizer: American society of gene & cell therapy 17th Annual meeting
  • Place of Presentation: the Marriott Wardman Park Hotel, Wahington DC, USA
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] Induction of Local OPMD Histopathology in Common Marmoset By rAAV1 and 8-Mediated Transduction. (2014)
  • Author(s): Hironori Okada, Hidetoshi Ishibashi,Hiromi Hayashita-Kinoh, Tomoko Chiyo, Chiaki Masuda, Yuko Nitahara-Kasahara, Shin’ichi Takeda, Takashi Okada
  • Organizer: American society of gene & cell therapy 17th Annual meeting
  • Place of Presentation: the Marriott Wardman Park Hotel, Wahington DC, USA
  • Year and Date: 2014-05-21 – 2014-05-24
• [Patent(Industrial Property Rights)] 移植用幹細胞及びその製造方法 (2014)
  • Inventor(s): 1) 岡田尚巳，笠原優子，武田伸一
  • Industrial Property Rights Holder: 1) 岡田尚巳，笠原優子，武田伸一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-05-21
  • Overseas
• [Patent(Industrial Property Rights)] 歯髄由来多能性幹細胞を含有する筋ジストロフィー治療剤 (2014)
  • Inventor(s): 2) 岡田尚巳，笠原優子，今川 究
  • Industrial Property Rights Holder: 2) 岡田尚巳，笠原優子，今川 究
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-11-14