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

Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilize a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing 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). Here we show early- and mid-treatment restores retinal function to near wild-type levels, specifically the sensitivity and signal fidelity of retinal ganglion cells, the output neurons of the retina. However, some anatomical defects persist. Late treatment retinas exhibit continued, albeit slowed, loss of sensitivity and signal fidelity among retinal ganglion cells, 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.

Methods
Raw, unprocessed microscopy images used to generate Figures 1-3.