Identification of drugs for Autosomal Dominant Optic Atrophy (ADOA): from ADOA RCGs models to microparticle-based drug delivery in an ADOA mouse model

Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy characterized by the progressive bilateral loss of vision for which no treatment currently exists. Mutations in the mitochondrial protein Optic Atrophy 1 (Opa1) are associated with ADOA which affect primarily Retinal Ganglion Cells (RGCs) causing optic nerve degeneration. RGCs carrying mutated Opa1 display excess autophagy, accumulation of autophagosomes in axonal hillocks and mitochondrial depletion along axons, all associated with loss of vision in an ADOA mouse model. Remarkably, genetic inhibition of autophagy restored both axonal mitochondria distribution and vision in ADOA mice. We hence reasoned that pharmacological inhibition of pathways connecting ADOA mitochondria to autophagy hyperactivation could restore axonal mitochondrial distribution in ADOA RGCs, ultimately interrupting the pathogenetic cascade that leads to blindness. To this end, we seek to identify drugs rescuing axonal mitochondrial content in ADOA RGCs, and to establish a novel drug delivery strategy to efficiently curtail visual loss in our ADOA mouse model. We are therefore generating the first immortalized RGC line to facilitate our in vitro studies and allow large scale drug screening on ADOA RGCs, as well as developing PLGA microparticles loaded with FK506, a calcineurin inhibitor known to regulate autophagy in RGCs, as means to deliver it to the retina by vitreous injection in the ADOA mouse model and verify if this strategy curtails the visual loss caused by loss of Opa1 in RGCs.