Visual function recovery by gene therapy targeting axon regeneration and remyelination

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09688
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: GUO Xiaoli 公益財団法人東京都医学総合研究所, 疾患制御研究分野, 主席研究員 (50443114)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 多発性硬化症 / ASK1 / グリア細胞 / TrkB / 遺伝子治療 / 軸索再生 / 神経保護 / 再髄鞘化

Outline of Final Research Achievements

We found that neuroinflammation was reduced in both the early and later stages of EAE in microglia/macrophage-specific ASK1 knockout mice, whereas only the later stage neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice. By using post-mortem multiple sclerosis tissue, ASK1 activation was found in active lesions of corpus callosum in both microglia/macrophages and astrocytes. Moreover, ASK1 activation in astrocytes was higher than that in microglia/macrophages, which were in line with our findings in EAE mice.
We invented a system (iTrkB) that results in constitutive activation without TrkB's ligands. iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic
nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

ASK1の細胞特異的な機能や既存薬剤による治療研究から網膜および視神経変性疾患など難病の発症メカニズムを
解明し、治療法の開発に有用な情報を提供した。特にMSによる視神経変性に対する治療薬の開発に有用である。
また緑内障の新たな治療法として常時活性型TrkB遺伝子治療システムを開発し報告した。このシステムは他の常時活性型受容体の作製にも活用できており汎用性がある。研究成果はPNASやMolecular therapyなどの学術誌に載せいた他、研究所HP、都立病院との共同研究会や産学連携研究会でも紹介し、研究成果を積極的に社会に公開する。