Advancing the Retinoic Acid Signaling Activator as a Novel Therapeutic in Mouse Models of Retinal
Degeneration
Retinitis
Pigmentosa (RP) is a genetic blindness disease that afflicts millions
worldwide. Although patients with this disease are born with the mutation that
causes it, the age of onset is often during childhood or adolescence. Usually,
a typical patient will go to the doctor’s office because of progressive night
vision problems, at which point, the underlying causal mutation may be
identified by genetic testing. While night vision impairment is troublesome, it
is not life-altering. Unfortunately, over the next years to decades, daylight
color vision progressively deteriorates, and some patients completely lose
their vision. Recent advancements in gene therapy have successfully corrected
one of the underlying mutations, leading to the preservation of vision in
patients suffering from RP. However, over 65 causal genes have been identified
that cause RP, and developing a gene therapy for each gene is not feasible.
Regardless of the gene mutation, the disease ultimately converges upon
progressive daylight color vision loss, which is due to the death of cone
photoreceptors, which are the cells in the back of the eye that allow us to
capture daylight color vision. The long-term goal of this project is to promote
cone photoreceptor survival in this disease in order to prolong healthy
daylight color vision for all patients suffering from RP. In our previous work,
we identified a new set of genes that, when activated, promotes cone
photoreceptor survival in a mouse model of RP. In this grant, we are proposing
three projects to take this study closer to the clinic. One, we will test a new
delivery method to activate these genes called AAV, which is the current
delivery method of choice for gene therapy. Second, we will reactivate these
surviving cones by using a bacterial ion pump that reacts to light. Third, we
will elucidate the mechanism by which RA signaling promotes cone survival by
dissecting the genes downstream of the signaling pathway. In sum, completing these projects will lead
us one step closer to prolonging healthy vision for all patients suffering from
RP.