Potential of Autophagy in Submacular Fibrosis in Neovascular Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is an eye disease that can lead to legal blindness and sight loss. The advanced form of AMD is categorized into dry and neovascular AMD. In neovascular AMD, the formation of new blood vessels disturbs the structure of the retina and induces an inflammatory response. Neovascular AMD is treated with antibodies and fusion proteins against vascular endothelial growth factor A (VEGFA) to inhibit neovascularization and delay sight loss. Nevertheless, a quarter of neovascular AMD patients do not respond to therapy. Many of these patients presented with subretinal fibrotic scars. Retinal pigment epithelium (RPE) cells, choroidal fibroblasts, and retinal glial cells play crucial roles in the formation of the fibrotic scar, as they can undergo a mesenchymal transition mediated by transforming growth factor beta and other molecules, leading to their transdifferentiation into myofibroblasts, which are critical players in subretinal fibrosis. The mesenchymal transition of retinal cells and dysfunction of the extracellular matrix, the two main aspects of fibrotic scar formation, are associated with impaired autophagy, an important player in AMD pathogenesis, but the causal relationship between autophagy and subretinal fibrosis is not known. This narrative/perspective review presents information on neovascular AMD, subretinal fibrosis, and autophagy and argues that impaired autophagy may be important for fibrosis-related resistance to anti-VEGFA therapy in neovascular AMD.