Development of a Topical Treatment for Cataract

DESCRIPTION provided by applicant Cataracts affect an estimated million people in the United States annually and account for million cases of blindness worldwide Although surgical cataract extraction is a reliable procedure that substantially improves visual acuity in of cases it places a large financial burden on healthcare systems In the United States alone the annual direct cost of cataract treatment is over $ billion higher than the combined costs to treat glaucoma advanced macular degeneration and diabetic retinopathy Moreover in much of the developing world surgical intervention is simply not accessible for patients Cataracts are caused when accumulated damage to the major lens crystallin proteins including crystallin cryAB causes their unfolding and subsequent assembly into insoluble amyloids There are no approved therapies to cure or reverse cataracts Pharmacological chaperones are small molecules that bind and stabilize the native form of a protein Our research team in collaboration with chemist Dr Jason Gestwicki UCSF and ophthalmologist Dr Usha Andley Washington University recently developed a novel differential scanning fluorimetry DSF platform and identified molecules that stabilize the native fold of cryAB Employing a small molecule from this screen we were able to demonstrate prevention of the aggregation of cryAB and fully dis assembled pre formed aggregates in vitro and an ophthalmic solution of the andquot hitandquot molecule compound completely restored transparency to the eyes of a mouse model of severe cataract Remarkably this effect occurred after only weeks of topical treatment mirroring the reversal kinetics observed in vitro To further develop this discovery we will Aim Design and synthesize an initial focused library of pharmacological small molecule chaperones to destabilize crystallin amyloid Aim Screen and select small molecule chaperones in vitro by assessing efficacy and therapeutic index Iterate library as required Aim Screen and select compounds in vivo for efficacy in a murine age related cataract model as well as hereditary cataract model PUBLIC HEALTH RELEVANCE Cataract is the most common form of vision loss worldwide impacting the vision of million individuals in the US and andgt million worldwide In this proposal we will pursue a safe effective topical treatment for the reversal of cataracts