Spatially and temporally regulated gene therapy using stress response promoter in retinal injury

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K20301
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: Tohoku University
• Principal Investigator: Fujita Kosuke 東北大学, 医学系研究科, 助手 (80708115)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 遺伝子治療 / 緑内障 / アデノ随伴ウイルス

Outline of Final Research Achievements

Retinal ganglion cell (RGC) degeneration is believed to underlie many ocular diseases including glaucoma. In these diseases, RGCs are affected unevenly, both spatially and temporally, such that healthy and unhealthy RGCs coexist in different patterns at different time points. We describe a temporally and spatially regulated AAV gene therapy aiming to reduce undesired off-target effects on healthy RGCs. The Mcp-1 promoter shown to be transcribed in stressed RGCs following murine optic nerve injury was combined with the neuroprotective transcription factor NRF2. In this model, Mcp-1-driven NRF2 expression targeting only stressed RGCs showed efficacy equivalent to non-selective CMV promoter-driven therapy for preventing RGC death. However, CMV promoter-mediated NRF2 transcription induced cellular stress responses and death of uninjured RGCs. Combining a stress-responsive promoter and therapeutic gene is a versatile strategy for specifically targeting cells at risk of degeneration.

Free Research Field

眼科学