mTOR 발현 제어를 통한 노인성 황반변성 치료 가능성 평가

Abstract

Purpose: The limitations of currently-employed treatments for wet age-related macular degeneration (AMD) include questions regarding long-term VEGF suppression and frequent injections negatively affecting patient compliance. Here, I explored the effects of a gene therapy designed to inhibit mTOR, a potential AMD therapeutic target, in a rat model of oxygen-induced retinopathy (OIR). Methods: Sprague-Dawley pups were used to generate the OIR model, with a recombinant adeno-associated virus expressing a shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection upon returning the rats to normoxia, with appropriate controls. Immunohistochemistry and TUNEL assays, as well as fluorescein angiography, were performed on transverse retinal sections and flat mounts, respectively, to determine the in vivo effects of mTOR inhibition with regard to wet AMD. Results: Compared to normal control rats, as well as OIR model animals that were either untreated (20.95±6.85), mock-treated (14.50±2.47), or injected with a control shRNA-containing virus vector (16.64±4.92), rAAV2-shmTOR-GFP (4.28±2.86, p=0.00103) treatment resulted in dramatically reduced neovascularization, the hallmark of wet AMD, as a percentage of total retinal area. These results mirrored quantifications of retinal avascular area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly greater therapeutic efficacy than the other treatments. The virus vector was additionally shown to reduce macrophage infiltration into retinal tissue and possess anti-apoptotic properties, both these processes being associated with wet AMD. Conclusions: Taken together, these results build upon the previous work to further demonstrate the strong promise of rAAV2-shmTOR-GFP as an effective and convenient gene therapy for wet AMD.