Development of regenerative medicine and cell therapy for inherited metabolic diseases using hypophosphatasia mice

• Project/Area Number: 25461564
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School
• Principal Investigator: Iijima Osamu 日本医科大学, 医学部, 助教 (40466206)
• Co-Investigator(Kenkyū-buntansha): MIYAKE Koichi 日本医科大学, 医学部, 准教授 (90267211) ; SHIMADA Takashi 日本医科大学, 医学部, 教授 (20125074)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Atsushi 日本医科大学, 医学部, 准教授 (10307952)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 再生・細胞医療 / 遺伝子治療 / 低ホスファターゼ症 / 骨髄幹細胞 / 造血幹細胞 / 骨格筋芽細胞 / レンチウイルスベクター / アルカリホスファターゼ / 低フォスファターゼ症 / アルカリフォスファターゼ

Outline of Final Research Achievements

We evaluated the feasibility of bone marrow stem cell-based enzyme replacement therapy (ERT) for hypophosphatasia model mice (Akp2-/- mice). Bone marrow stem cells transduced with bone-targeted form of tissue-nonspecific alkaline phosphatase (TNALP-D10) gene was intravenously transplanted into neonatal Akp2-/- mice on day 2 after birth. The treated Akp2-/- mice showed significantly prolonged survival with improved bone mineralization. These results provided us important insight regarding development of novel regenerative and cell therapy for inherited metabolic diseases including hypophosphatasia.

Research Products

• [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, J. L., Shimada, T.,Okada, T.
  • Journal Title: Molecular Therapy- Methods & Clinical Development Volume: 3 Pages: 15059-15059
  • DOI: 10.1038/mtm.2015.59
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prevention of Lethal Murine Hypophosphatasia by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells. (2015)
  • Author(s): Iijima O, Miyake K, Watanabe A, Miyake N, Igarashi T, Kanokoda C, Nakamura-Takahashi A, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millán JL, Okada T, Shimada T.
  • Journal Title: Hum Gene Ther. Volume: 26 Issue: 12 Pages: 801-12
  • DOI: 10.1089/hum.2015.078
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Perinatal hypophosphatasia caused by uniparental isodisomy. (2014)
  • Author(s): Watanabe A, Satoh S, Fujita A, Naing BT, Orimo H, Shimada T.
  • Journal Title: Bone Volume: 60 Pages: 93-97
  • DOI: 10.1016/j.bone.2013.12.009
  • Peer Reviewed
• [Presentation] Gene therapy to rescue lethal hypophosphatasia model mice by adeno-associated virus-mediated muscle transduction of bone-targeted alkaline phosphatase. (2015)
  • Author(s): Nakamura A, Miyake K, Watanabe A, Hirai Y, Iijima O, Miyake N, Adachi K, Nitahara-Kasahara Y, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millan JL, Shimada T, Okada T.
  • Organizer: 第21回日本遺伝子治療学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府）
  • Year and Date: 2015-07-23
  • Int'l Joint Research
• [Presentation] Rescue of lethal murine hypophosphatasia using genetically modified bone marrow cells expressing bone-targeted tissue non-specific alkaline phosphatase. (2015)
  • Author(s): Iijima O, Miyake K, Watanabe A, Miyake N, Igarashi T, Kanokoda C, Nakamura-Takahashi A, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millan JL, Okada T, Shimada T.
  • Organizer: 第11回ALPS研究会
  • Place of Presentation: 日本女子大学（東京都）
  • Year and Date: 2015-07-18
• [Presentation] Long-term enzyme replacement therapy for hypophosphatasia by muscle-directed expression of bone targeted alkaline phosphatase using self-complementary AAV8 vector. (2015)
  • 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, Millan JL, Shimada T, Okada T.
  • Organizer: 第11回ALPS研究会
  • Place of Presentation: 日本女子大学（東京都）
  • Year and Date: 2015-07-18
• [Presentation] Prolonged Survival and Improved Phenotypes of Lethal Hypophosphatasia Model Mice By Adeno-Associated Virus Mediated Muscle Transduction of Bone-Targeted Alkaline Phosphatase. (2015)
  • Author(s): Nakamura A, Miyake K, Watanabe A, Hirai Y, Miyake N, Iijima O, Adachi K, Kinoshita H, Noguchi T, Abe S, Shimada T, Okada T.
  • Organizer: 18th American Society of Gene and Cell Therapy Annual Meeting
  • Place of Presentation: Hyatt Regency New Orleans（New Orleans, LA）
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Gene Therapy Improves Dental Manifestations in Akp2-/- Hypophosphatasia Mice. (2015)
  • Author(s): Okawa R, Iijima O, Kishino M, Okawa H, Toyosawa S, Shimada T, Okada T, Ooshima T, Nakano K.
  • Organizer: International Association for Dental Research General Session (93th)
  • Place of Presentation: Hynes Convention Center (Boston, MA)
  • Year and Date: 2015-03-11 – 2015-03-14
• [Presentation] Rescue of lethal hypophosphatasia model mice by adeno-associated virus mediated muscle specific expression of bone targeted alkaline phosphatase. (2014)
  • Author(s): Nakamura A, Iijima O, Miyake K, Watanabe A, Hirai Y, Kinoshita H, Noguchi T, Abe S, Okada T, Shimada T.
  • Organizer: American Society of Human Genetics Annual Meeting (64th)
  • Place of Presentation: San Diego Convention Center（San Diego, CA）
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] Neonatal transplantation of lentivirally transduced bone marrow cells for the treatment of lethal hypophosphatasia mice. (2014)
  • Author(s): Iijima O, Miyake K, Watanabe A, Nakamura A, Igarashi T, Kanokoda C, Kinoshita H, Noguchi T, Abe S, Okada T, Shimada T.
  • Organizer: 日本遺伝子治療学会学術集会（第20回）
  • Place of Presentation: 東京慈恵会医科大学（東京都）
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Improvement of hypophosphatasia model mice by muscle specific expression of bone targeted alkaline phosphatase using self-complementary AAV8 vector. (2014)
  • Author(s): Nakamura A, Iijima O, Miyake K, Watanabe A, Hirai Y, Kinoshita H, Noguchi T, Abe S, Okada T, Shimada T.
  • Organizer: 日本遺伝子治療学会学術集会（第20回）
  • Place of Presentation: 東京慈恵会医科大学（東京都）
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] 低フォスファターゼ症マウスに対するex vivo遺伝子治療法の検討 (2013)
  • Author(s): 飯島 修、三宅弘一、中村有希、鹿子田千津、五十嵐勉、渡邉 淳、島田 隆
  • Organizer: 第58回日本人類遺伝学会
  • Place of Presentation: 江陽グランドホテル（宮城県仙台市）
• [Presentation] Bone marrow cell based enzyme replacement prolongs survival and improves disease phenotypes in a mouse model of lethal hypophosphatasia (2013)
  • Author(s): Iijima O, Miyake K, Nakamura A, Igarashi T, Kanokoda C, Watanabe A, Shimada T
  • Organizer: 55th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Ernest N. Morial Convention Center (New Orleans, LA, USA)