Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Abstract

AbstractRetinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss and eventual blindness. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilized a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing the variables that complicate the ability to answer this vital question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restored retinal function to near wild-type levels, specifically the sensitivity and signal fidelity of retinal ganglion cells (RGCs), the ‘output’ neurons of the retina. However, some anatomical defects persisted. Late treatment retinas exhibited continued, albeit slowed, loss of sensitivity and signal fidelity among RGCs, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision.