Small molecule activators of alpha crystallin for non surgical treatment of cataracts

Project Summary Cataract the clouding of the eye lens is responsible for of world blindness According to World Health Organization nearly million people are bilaterally blind from cataract in the world Cataract is easily treated by surgery and is considered as one of the most cost effective interventions Although cataract surgery is generally considered to be safe there are significant complications i of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment ii have retinal detachments iii are hospitalized for corneal edema or require corneal transplantation and iv about are presented with endophthalmitis In addition in many remote and poor areas of the developing and under developed regions of the world people still remain blind from cataract primarily due to lack of access to eye care As a result of which cataract related blindness is as high as or more in poor and remote regions of the world compared to only in developed countries Alpha crystallin AC is one of the three major eye lens crystallins and is a representative member of the small heat shock protein sHsp family AC serves as molecular chaperone protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation It is well established that chaperone like activity CLA of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataract The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A chain AAC and can delay cataract formation in preclinical models It has been estimated that delaying cataract formation by years can reduce the vision care expense by In addition our preliminary data supports the hypothesis that drug like synthetic small molecules representing the CAP series specifically increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model Therefore the basic goal of our proposal is to discover potent small molecule activators of AAC to be developed into safe and cost effective non surgical treatment to delay and or reverse cataract related blindness and the specific aims are Aim Structure based design commercial acquisition and synthesis of small molecule activators of AAC Aim Assess therapeutic efficacy of AAC activators from Specific Aim using in vitro glycation and ex vivo cell culture experiments and Aim Assess compounds from Specific Aim for preliminary in vivo safety and efficacy using ex vivo organ culture cataract models The milestone for the Phase I studies is to discover potent activators of AAC with EC uM shown to be safe in rabbit eye lens maintain clarification of lens for days in organ culture experiments with concomitant compound uptake and decrease in aggregated forms of lenticular client protein levels Project Narrative Cataracts are the leading cause of blindness worldwide particularly in low and middle income countries Data dating back to the beginning of this millennium showed that of blindness in Africa and in South East Asia is attributable to cataracts The only treatment currently available is surgical extraction of the lens and replacement with an interocular lens that is accompanied by a high public health burden This proposal provides an innovative non surgical approach to address this public health burden