Vision rescue via chemically engineered endogenous retinal ganglion cells

Abstract

Loss of retinal ganglion cells (RGCs) is the final common end point for many optic neuropathies, ultimately leading to irreversible vision loss. Endogenous RGC regeneration from Müller cells presents a promising approach to treat these diseases, but mammalian retinas lack regenerative capacity. Here, we report a small molecule cocktail that causes endogenous Müller cell proliferation, migration, and specification to newly generated chemically induced RGCs (CiRGCs) in NMDA injured mice retina. Notably, regenerated CiRGCs extend axons towards optic nerve, and rescue vision post-NMDA treatment. Moreover, we successfully reprogrammed human primary Müller glia and fibroblasts into CiRGCs using this chemical-only approach, as evidenced by RGC-specific gene expression and chromatin signature. Additionally, we show that interaction between SOX4 and NF-kB determine CiRGC fate from Müller cells. We anticipate endogenous CiRGCs would have therapeutic potential in rescuing vision for optic nerve diseases.