Pharmacological restoration of transparency in cataract

Summary Cataracts are the leading cause of blindness in the world, currently treatable only with surgery. The molecular chaperone α ‐crystallin helps to maintain the transparency of the crystallin lens. The soluble fraction of this protein decreases with aging, a phenomenon that is associated with presbyopia and age‐related cataract. Moreover, destabilizing mutations in α ‐crystallin are associated with early onset, hereditary cataract. We hypothesized that a ligand that binds and stabilizes α ‐crystallin may prevent its aggregation, representing a strategy for preventing or even treating cataract. We developed computational and experimental high‐throughput screening techniques to identify small molecule ligands for α ‐crystallin. These molecules prevented and reversed protein aggregation and improved lens transparency when dosed to mice with cataracts. The presentation will include a discussion of the potential of the molecular chaperone α ‐crystallin as a target for therapeutic intervention in cataracts. The safety, efficacy, bioavailability, and mechanism of the active compounds will be discussed, along with considerations of how a potential pharmacological intervention might complement the existing surgical treatment paradigm.