Developing a new therapeutic agent for retinal ciliopathies

The ciliopathies are a group of andgt overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure the basal body Although individually rare this group contributes significantly to the population genetic disease burden with some estimates placing their combined incidence to as much as Importantly although some ciliopathies are lethal most patients survive to adulthood where they are faced with profound clinical challenges of managing multiple symptoms that include retinal degeneration neurocognitive defects obesity diabetes and psychiatric illness At present there are no treatments and minimal palliative options This proposal aims to take the first steps towards developing clinical assets that aspire to slow or arrest degenerative aspects of the ciliopathy pathology Our work is grounded on two key observations First several recent studies have shown that ciliopathy proteins regulate the selective proteasome mediated degradation of signaling components Second a recent genome wide suppressor screen in human cells showed that suppression of the deubiquitinase USP could ameliorate ciliopathy induced signaling defects Validating these observations suppression or deletion of USP in three zebrafish models of Bardet Biedl syndrome BBS a model ciliopathy attenuated several pathognomonic phenotypes most prominently structural and trafficking defects in the photoreceptor with no apparent toxic side effects These discoveries and models have been foundational to the formation of Rescindo Therapeutics a biotech company whose mission is to develop suppressor screens and derivative molecules as rational therapeutic agents During the past year Rescindo has developed two reagents of potential clinical utility an adeno associated virus expressing shRNAs against human and mouse USP and antisense oligonucleotides against the same target Here we aim to test the utility of these tools in human cells and in mouse models as a pre amble to designing clinical trials Within our company we will test the efficacy of each reagent to attenuate paracrine signaling in primary cells derived from patients with mutations in three different BBS genes In parallel and in collaboration with the Arshavsky laboratory at Duke we will test whether each reagent can have a quantitative benefit in attenuating or extinguishing the progressive loss of photoreceptors in a mouse mode of BBS Successful completion of these studies will provide the necessary data for the rational design of future trials and will represent a key step towards developing the first therapeutic assets for ciliopathies The ciliopathies are a group of andgt overlapping clinical disorders with no therapeutic options This proposal will support the collaborative effort between Rescindo Therapeutics and Duke University to develop two molecules of therapeutic potential for this group of disorders and to generate the efficacy data in human cells and mouse models that are necessary for the eventual development of clinical trials