Gene Expression and Editing in Mammalian Retinal Ganglion Cells

Retinal ganglion cells (RGCs) are the only projection neurons in retina, responsible for collecting all visual information processed by other retinal neurons and relaying that information to the rest of the brain through the optic nerve, through which all RGC axons traverse. The optic nerve is highly vulnerable to damage by traumatic injury, inflammation, ischemia, toxicity, hereditary deficits, and high intraocular pressure (IOP), any of which can cause retrograde RGC death. Optic neuropathy can also be associated with other central nervous system (CNS) neurodegenerative diseases. Lack of effective neuroprotective or regenerative therapy for RGCs and optic nerve significantly impedes preservation of vision in patients with optic neuropathies, and novel treatments are desperately needed. There are both challenges and opportunities for the development of gene therapies targeting RGCs. RGCs are a heterogeneous neuronal population; understanding how diseases and treatments affect different RGC types and how this translates between species is vital to therapeutic design. Advances in gene therapy and clustered regularly interspaced short-palindromic repeats (CRISPR)-mediated gene editing approaches and the early success of retinal gene therapy clinical trials are encouraging and suggest that the treatment of degenerative conditions affecting RGCs is achievable in the near future. Continued development of viral and nonviral vectors that improve the efficiency and specificity of therapeutic gene expression in RGCs, combined with deeper understanding of disease mechanisms, will be critical for progressing toward these goals.