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.