Development of a novel therapy (gene therapy) for metachromatic leukodystrophy

• Project/Area Number: 18K07859
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nippon Medical School
• Principal Investigator: Miyake Noriko 日本医科大学, 医学部, テクニカルスタッフ (00421206)
• Co-Investigator(Kenkyū-buntansha): 三宅 弘一 日本医科大学, 医学部, 教授 (90267211)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 遺伝子治療 / 異染性白質ジストロフィー / アデノ随伴ウイルス / ライソゾーム病 / 中枢神経病変 / リソゾーム病 / 異染性白質ジストロフィ－

Outline of Final Research Achievements

Enzyme replacement therapy is a promising treatment for lysosomal disease, but the presence of the blood-brain barrier is generally a major obstacle to effective treatment strategies for lysosomal disease associated with CNS degeneration. The aim of this study is to develop an innovative therapy for the non-invasive and safe long-term enzyme replacement therapy for CNS disease of metachromatic leukodystrophy (MLD), which is associated with extensive neurodegeneration throughout the brain.
We have reported the efficacy of intrathecal administration of AAV vectors in the treatment of an adult mouse model of MLD, showing improvement of CNS lesions, and confirmed that intrathecal administration of AAV vectors is more effective than intravenous administration of AAV vectors, requiring less vector.

Academic Significance and Societal Importance of the Research Achievements

本研究では脳全体の広範な神経変性を伴う、異染性白質ジストロフィーをモデルとし、非侵襲的かつ安全で中枢神経組織に長期の酵素補充療法が出来る治療法の開発を行った。
髄腔内投与することにより、より少ないベクター量で中枢神経疾患への治療が可能になり、ライソゾーム病のみならず、筋萎縮性側索硬化症、アルツハイマー病などの様々な中枢神経病変を伴う疾患に応用が可能なると示唆された。

Research Products

• [Journal Article] 1.Treatment with bone maturation and average lifespan of HPP model mice by AAV8-mediated neonatal gene therapy via single muscle injection. (2021)
  • Author(s): Matsumoto T, Miyake K, Miyake N, Iijima O, Adachi K, Narisawa S, Millan JL, Orimo H, Shimada T.
  • Journal Title: Mol Ther Methods Clin Dev. Volume: 22 Pages: 330-337
  • DOI: 10.1016/j.omtm.2021.06.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 2.Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. (2021)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Suzuki H, Shimada T.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-99979-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new method for in vivo targeted gene transfer into oligodendrocytes using adenoviral and HIV vectors. (2021)
  • Author(s): 1.Miyake K, Miyake N and Shimada T.
  • Journal Title: Biomedical J. of Sci. & Tec. Res. Volume: 3 Issue: 3 Pages: 31379-31385
  • DOI: 10.26717/bjstr.2021.39.006306
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 1.TERT and TERC mutations detected in cryptic dyskeratosis congenita suppress telomerase activity. (2020)
  • Author(s): Terada K, Miyake K, Yamaguchi H, Miyake N, Yamanaka K, Kojima S, Ito E, Inokuchi K, Okada T.
  • Journal Title: Int J Lab Hematol. Volume: - Issue: 3 Pages: 316-321
  • DOI: 10.1111/ijlh.13176
  • Int'l Joint Research
• [Journal Article] 2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts. (2019)
  • Author(s): Haginiwa S, Sadahiro T, Kojima H, Isomi M, Tamura F, Kurotsu S, Tani H, Muraoka N, Miyake N, Miyake K, Fukuda K, Ieda M.
  • Journal Title: Biochem Biophys Res Commun Volume: 513 Issue: 4 Pages: 1041-1047
  • DOI: 10.1016/j.bbrc.2019.04.087
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 異染性白質ジストロフィーの遺伝子治療 (2022)
  • Author(s): 三宅 紀子, 三宅 弘一, 酒井 真志人, 島田 隆
  • Organizer: The 28th Annual Meeting of Japan Society of Gene Therapy
  • Invited
• [Presentation] Direct comparison between single-stranded and self-complementary type 9 AAV vector to treat adult MLD model mice by intravenous injection (2018)
  • Author(s): Noriko Miyake, Koichi Miyake, Motoko Yamamoto, Takashi Shimada, Takashi Okada
  • Organizer: The 2４th Annual Meeting of Japan Society of Gene Therapy
• [Presentation] Intravitreal injection of AAV vector in cynomolgus monkeys affects neutralizing antibody titer against AAV in the serum (2018)
  • Author(s): Tsutomu Igarashi, Kazuhisa Takahashi, Koichi Miyake, Maika Kobayashi, Chiemi Yaguchi, Noriko Miyake, Shuhei Kameya, Hiroshi Takahashi, Takashi Okada
  • Organizer: The 2４th Annual Meeting of Japan Society of Gene Therapy
• [Book] Neonatal Gene Therapy for Inherited Disorders. Selected Topics in Neonatal Care. (2018)
  • Author(s): Miyake K, Miyake N, Shimada T.
  • Total Pages: 9
  • Publisher: InTech