Project Details
Projekt
RPE plasticity in the context of neurodegenerative diseases: Understanding the limits, pushing the boundaries
Applicant
Professorin Dr. Susanne Koch
Subject Area
Ophthalmology
Pharmacology
Pharmacology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 513025799
Retinitis pigmentosa (RP) is a progressive retinal degenerative disease affecting teenagers and adults, and the most common cause of inherited blindness. The disease pathology is driven by mutations in the light-sensitive rod photoreceptors, which trigger their death and, secondarily, the death of cone photoreceptors. The photoreceptor pathology also drives changes in the neighboring retinal pigment epithelium (RPE), which have not been well characterized. 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 of these goals are achievable, even at late disease stages. On the other hand, we show that in the post-gene-therapy environment, RPE continues to undergo changes, 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 (Aim 1) and functional (Aim 2) 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 metabolites and metabolic pathways in RPE that are associated with RP disease or genetic rescue (Aim 3). Lastly, we will provide proof of concept for a novel therapeutic vector, and validate genetic rescue experiments (Aim 4). From the resulting data, we expect to be able to identify novel markers of disease progression in RPE cells and rescue. These RPE features could potentially be used to develop new therapeutics with improved efficacy and sustainability, or could represent potential therapeutic targets to increase efficacy and sustainability of gene therapy.
DFG Programme
Research Units
