ABSTRACT
Inherited retinal dystrophies (IRDs) cause progressive, irreversible vision loss and most are currently untreatable.
Pathogenic variants in over 300 genes are implicated in IRDs, and variants within a single gene can cause
diverse retinal phenotypes, which makes therapeutic development challenging. As an alternative to genetic
strategies which are disease-specific, we propose that gene agnostic approaches using small molecule drugs
have the potential to treat multiple IRDs independent of their genetic etiology. Our studies on mouse models of
IRDs have identified cholesterol and ceramide as common pathogenic drivers of retinal pigment epithelium
(RPE) dysfunction that culminates in retinal degeneration. Accumulation of these lipids facilitates complement-
induced mitochondrial injury in the RPE, infiltration of microglia into the sub-retinal space, and eventually
photoreceptor loss. Here, we will evaluate therapeutic efficacy of two small molecule drugs, a clinically approved
bisphosphonate that inhibits cholesterol biosynthesis and ceramide generation (Aim 1) and a pan-adiponectin
receptor agonist that stimulates ceramidase activity and promotes mitochondrial biogenesis (Aim 2), in mouse
models of Stargardt disease and Batten disease. We will test the hypothesis that these drugs act as “triple
threats” by lowering cholesterol and ceramide and protecting RPE mitochondria, thereby preventing microglial
activation and retinal degeneration. We will use cutting-edge techniques such as intravital imaging of drug
distribution, super-resolution imaging of mitochondrial dynamics in the living mouse retina, lipidomics,
transcriptomics, and noninvasive evaluation of retinal structure and function to establish the ability of these drugs
to safeguard the RPE and retina in disease models. These drugs have documented safety profiles and reach
the retina in therapeutically effective concentrations after systemic administration, circumventing the need
for invasive delivery. Therefore, they hold immense promise as novel, powerful, gene-independent
therapeutics for IRDs.