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Development of novel gene therapy for CNS disorders of lysosomal diseases

Research Project

Project/Area Number 24591529
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionNippon Medical School

Principal Investigator

MIYAKE NORIKO  日本医科大学, 医学部, その他 (00421206)

Co-Investigator(Kenkyū-buntansha) MIYAKE Koichi  日本医科大学, 医学部, 准教授 (90267211)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords異染性白質ジストロフィー / 遺伝子治療 / アデノ随伴ウイルス / 中枢神経病変 / 新生児治療 / AAV vector
Outline of Final Research Achievements

We examined the feasibility of adeno-associated viral serotype-9 (AAV9)-mediated systemic neonatal gene therapy of metachromatic leukodystrophy (MLD) mice to treat central nervous system (CNS) disorders. AAV9 vector expressing human arylsulfatase A (AAV9/ASA) was injected into the jugular vein of newborn MLD mice. Global gene transfer into the brain, across the blood brain barrier, and long-term ASA expression in the CNS were detected in treated mice. Significant inhibition of the accumulation of sulfatide (Sulf) in the brain was confirmed by Alcian blue staining and biochemical analysis of the Sulf content. In a behavior test, treated mice showed a greater ability to traverse narrow balance beams than untreated mice. These data clearly demonstrate that MLD mice can be effectively treated through neonatal systemic injection of AAV9/ASA. Thus, AAV9 mediated systemic neonatal gene therapy is useful to treat various CNS disorders.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (25 results)

All 2014 2013 2012

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 2 results) Presentation (15 results) Book (1 results)

  • [Journal Article] Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector.2014

    • Author(s)
      Miyake N, Miyake K, Asakawa N, Yamamoto M, Shimada T.
    • Journal Title

      Gene Ther.

      Volume: 印刷中 Issue: 4 Pages: 427-433

    • DOI

      10.1038/gt.2014.17

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] nhibition of S100A6 induces graft versus leukemia effects in MLL/AF4-positive ALL in human PBMC-SCID mice.2014

    • Author(s)
      Tamai.H, Miyake K, Yamaguchi H, Shimada T, Dan K, Inokuchi K.
    • Journal Title

      Bone Marrow Transplantation

      Volume: 49(5) Issue: 5 Pages: 699-703

    • DOI

      10.1038/bmt.2014.18

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] siRNA Knockdown of Tissue Inhibitor of Metalloproteinase-1 in Keloid Fibroblasts Leads to Degradation of Collagen Type I2014

    • Author(s)
      Aoki M, Miyake K, Ogawa R, Dohi T, Akaishi S, Hyakusoku H, Shimada T.
    • Journal Title

      J Invest Dermatol.

      Volume: 134 Issue: 3 Pages: 818-826

    • DOI

      10.1038/jid.2013.396

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar purkinje cells2014

    • Author(s)
      Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H.
    • Journal Title

      Cerebellum

      Volume: 13 Issue: 1 Pages: 29-41

    • DOI

      10.1007/s12311-013-0516-5

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells2014

    • Author(s)
      Komiyama H, Miyake K, Asai K, Mizuno K, Shimada T.
    • Journal Title

      Cell Biochem Funct.

      Volume: 32 Issue: 1 Pages: 70-76

    • DOI

      10.1002/cbf.2973

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability2013

    • Author(s)
      Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H.
    • Journal Title

      Brain

      Volume: 136 Issue: 9 Pages: 2738-2750

    • DOI

      10.1093/brain/awt191

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Role of survivin in acute lung injury: Epithelial cells of mice and humans2013

    • Author(s)
      Terasaki Y, Terasaki M, Urushiyama H, Nagasaka S,Kungi S, et al.
    • Journal Title

      Lab Invest

      Volume: 93 Issue: 10 Pages: 1147

    • DOI

      10.1038/labinvest.2013.103

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Direct comparison of administration routes for AAV8-mediated ocular gene therapy2013

    • Author(s)
      Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H.
    • Journal Title

      Curr Eye Res.

      Volume: 38 Issue: 5 Pages: 569-577

    • DOI

      10.3109/02713683.2013.779720

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification.2012

    • Author(s)
      Miyake K, Miyake N, Yamazaki Y, Shimada T, Hirai Y.
    • Journal Title

      J Nippon Med Sch.

      Volume: 79 Pages: 394-402

    • NAID

      130004057397

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Trans-BBB gene therapy for metachromatic leukodystrophy using self-complementary type 9 AAV vector2014

    • Author(s)
      Miyake N, Miyake K, Yamamoto M, Okada T, Shimada T.
    • Organizer
      The 20th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      東京
    • Year and Date
      2014-08-06 – 2014-08-08
    • Related Report
      2014 Annual Research Report
  • [Presentation] Successful Treatment of Adult MLD Model Mice By Intravenous Injection of Self-Complementary Type 9 AAV Vector Expressing ASA2014

    • Author(s)
      Miyake N, Miyake K, Yamamoto M, Shimada T.
    • Organizer
      17th Annual Meeting of the American Society of Gene & Cell Therapy
    • Place of Presentation
      Washington DC
    • Year and Date
      2014-05-21 – 2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] Minimally invasive gene therapy of MLD model mice by intrathecal and intravenous injection of AAV9 vector.2014

    • Author(s)
      Noriko Miyake, Koichi Miyake, and Takashi Shimada
    • Organizer
      10th WORLDSymposium™ 2014
    • Place of Presentation
      San Diego,CA
    • Related Report
      2013 Research-status Report
  • [Presentation] Long−Term Secretion of Arylsulfatase A without Antibody Formation after AAV Mediated Neonatal Gene Transfer into MLD Model Mice.2013

    • Author(s)
      Miyake N, Miyake K, Yamamoto M and Shimada T.
    • Organizer
      16th Annual Meeting of the American Society of Gene & Cell Therapy.
    • Place of Presentation
      Salt Lake City, Utah
    • Related Report
      2013 Research-status Report
  • [Presentation] Adeno−Associated Vector (Type 8)−Mediated Expression of siRNA Targeting Vascular Endothelial Growth Factor Efficiently Inhibits Neovascularization in a Murine Choroidal Neovascularization Model.2013

    • Author(s)
      Igarashi T, Miyake K, Miyake N, Iijima O, Yaguchi C, Shimada T and Takahashi H.
    • Organizer
      16th Annual Meeting of the American Society of Gene & Cell Therapy.
    • Place of Presentation
      Salt Lake City, Utah
    • Related Report
      2013 Research-status Report
  • [Presentation] Tolerance induction to arylsulfatase A by AAV mediated neonatal gene transfer into MLD model mice.2013

    • Author(s)
      Miyake N, Miyake K, Yamamoto M and Shimada T.
    • Organizer
      The 19th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      Okayama
    • Related Report
      2013 Research-status Report
  • [Presentation] siRNA Targeting Vascular Endothelial Growth Factor by adeno-associated vector (type 8) efficiently inhibits Neovascularization in a Murine Choroidal Neovascularization Model.2013

    • Author(s)
      Igarashi T, Miyake N, Iijima O, Yaguchi C, Shimada T, Takahashi H and Miyake K.
    • Organizer
      The 19th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      Okayama
    • Related Report
      2013 Research-status Report
  • [Presentation] Disruption of metabotropic glutamate receptor signaling and rescue through intravascular administration of AAV9 in a mouse model of spinocerebellar ataxia type 3.2013

    • Author(s)
      Konno A, Shuavaev AN, Miyake N, Miyake K, Yanagi S, Shimada T, Hirai H.
    • Organizer
      The 19th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      Okayama
    • Related Report
      2013 Research-status Report
  • [Presentation] Robust and cell type-specific transgene expression by applying tetracycline-controlled system to AAV9.2013

    • Author(s)
      Yamaguchi T, Konno A, Miyake N, Miyake K, Shimada T, Hirai H.
    • Organizer
      The 19th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      Okayama
    • Related Report
      2013 Research-status Report
  • [Presentation] miR-7aは電位依存性ナトリウムチャネルβ2サブユニットの発現調節により慢性期神経障害性疼痛を緩和する2013

    • Author(s)
      坂井 敦、齋藤文仁、三宅紀子、三宅弘一、島田 隆、鈴木秀典
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡国際会議場
    • Related Report
      2012 Research-status Report
  • [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector2012

    • Author(s)
      Noriko Miyake, Koichi Miyake, Atsushi Sakai, Motoko Yamamoto, Ayumi Endo, Hidenori Suzuki, Takashi Shimada
    • Organizer
      15th Annual Meeting of the American Society of Gene & Cell Therapy
    • Place of Presentation
      Philadelphia, Pennsylvania
    • Related Report
      2012 Research-status Report
  • [Presentation] Successful treatment of adult MLD model mice by intrathecal administration of AAV9 vector2012

    • Author(s)
      Noriko Miyake, Koichi Miyake, Atsushi Sakai, Motoko Yamamoto, Ayumi Endo, Hidenori Suzuki, Takashi Shimada
    • Organizer
      The 18th Annual Meeting of Japan Society of Gene Therapy
    • Place of Presentation
      Kumamoto
    • Related Report
      2012 Research-status Report
  • [Presentation] AAV9 mediated gene therapy of MLD model mice2012

    • Author(s)
      Noriko Miyake, Koichi Miyake, Atsushi Sakai, Motoko Yamamoto, Ayumi Endo, Hidenori Suzuki, Takashi Shimada
    • Organizer
      20th Annual Meeting of the European Society of Gene & Cell Therapy
    • Place of Presentation
      Versailles, France
    • Related Report
      2012 Research-status Report
  • [Presentation] DRG神経におけるmiR-7a過剰発現は神経障害性疼痛を特異的に抑制する2012

    • Author(s)
      坂井敦、齋藤文仁、三宅紀子、三宅弘一、島田隆、鈴木秀典
    • Organizer
      第35回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場
    • Related Report
      2012 Research-status Report
  • [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector2012

    • Author(s)
      Noriko Miyake, Koichi Miyake, Atsushi Sakai, Motoko Yamamoto, Ayumi Endo, Hidenori Suzuki, Takashi Shimada
    • Organizer
      第4回国際ライソゾーム病フォーラム・第17回日本ライソゾーム病研究会
    • Place of Presentation
      東京プリンスホテル
    • Related Report
      2012 Research-status Report
  • [Book] Novel gene therapy approaches2013

    • Author(s)
      Miyake K, Shimada T.
    • Total Pages
      440
    • Publisher
      InTech
    • Related Report
      2013 Research-status Report

URL: 

Published: 2013-05-31   Modified: 2019-07-29  

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