Chemically induced in vivo retinal neuron regeneration rescues vision in mice

ABSTRACT Loss of retinal ganglion cells (RGCs) is a major cause of vision loss in optic neuropathies such as glaucoma, with no available treatments to restore vision. In teleost fish, Müller glia possesses a remarkable regenerative capacity to replace lost RGCs and restore vision—a capability lacking in mammals. Here, we have identified a six-small molecule cocktail (6C) that induces in vivo reprogramming of retina resident Müller glia into retinal neurons within the ganglion cell layer (GCL) following RGC injury. We name these cells “chemically induced GCL neurons (CiGN)”. During reprogramming process, Müller glia re-enters the cell cycle in the inner nuclear layer, asymmetrically divide, proliferate and migrate to the GCL as SOX2 + and SOX2 − intermediates, exit the cell cycle, and differentiate into CiGN cells—mirroring some aspects of retinal regeneration seen in teleost fish. Functionally, 6C treatment restores long-term visual functions in rodent models of ocular hypertension and NMDA-induced RGC injury. Notably, 6C induces axon extension along the optic nerve and establish connections to the lateral geniculate nucleus (LGN) possibly through a neuronal relay mechanism. These findings highlight small molecule mediated cellular reprogramming as a potential therapeutic strategy for vision restoration in glaucoma and other optic neuropathies that affects millions of children and adults worldwide.