Project 7 - RPE plasticity in the context of neurodegenerative disease: Understanding the limits, pushing the boundaries

Retinitis pigmientosa (RP) disease pathology is driven by mutations in the light-sensitive rod photoreceptors, which trigger their death and, secondarily, cone photoreceptor degeneration and RPE remodeling. RPE and photoreceptors are structurally, functionally, and metabolically coupled. Our work shows that this interface is disrupted in RP. The best hope for a cure for RP lies in gene therapy. 

However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, the goal of gene therapy is to halt further photoreceptor degeneration and functional loss. Our work in various mouse models demonstrates that both goals are achievable, even at late disease stages. On the other hand, we show that in the post-gene-therapy environment, RPE continues to change, suggesting that the rescued retinas, at least RPE, have not achieved a stable, albeit new, homeostasis but instead continue to remodel and/or degrade. Whether these ongoing RPE changes impact the sustainability of gene rescue is not clear. Data from clinical trials for retinal degenerative diseases expose similar sustainability concerns. 

Our goal is to identify aspects of RPE structural and functional remodeling in RP retinas that are rescued by gene therapy treatment at early, mid, and late disease stages. In parallel, we will identify changes in metabolic pathways in RPE that are associated with RP disease or genetic rescue. Lastly, we will provide proof of concept for a novel therapeutic vector and validate genetic rescue experiments.