Epigenetic Reprogramming- A Novel Gene Therapy to Rejuvenate Injury-Induced Dysfunction of Retinal Ganglion Cells in Optic Neuropathies

NAION (Non-Arteritic Anterior Ischemic Optic Neuropathy) and glaucoma are optic neuropathies with different pathophysiology but a common endpoint, the apoptosis of retinal ganglion cells (RGCs). Our recently published studies indicate ganglion cell injury triggers epigenetic changes consistent with those associated with aging (ie the "epigenetic clock"). We developed a novel gene therapy called "epigenetic reprogramming" using the AAV2 (adeno-associated virus) vector to transiently express three reprogramming genes [OSK: Oct4, Sox2, Klf4)] that remove epigenetic signals associated with aging. Reprogramming RGCs in aging mice and mice with microbead-induced elevated pressure glaucoma restored lost visual function as measured by pERG and OMR (Optomotor Reflex) and coincided with restoring a "young" transcriptome and methylome in RGCs. Importantly, delivery and activation of OSK reprogramming genes occurred after loss of RGC function had already occurred. In the current study, we determined the duration of restored visual function and the long-term safety of OSK gene therapy.