Drug Screening Platform in the Light-Responsive Human Eye

Blinding diseases rob independence from millions of people in aging societies with poor metabolic and cardiovascular health. There are currently almost 1,000 planned or active clinical trials for investigational new drugs (INDs) to address AMD, diabetic retinopathy, glaucoma or inherited retinal degenerations. In addition, stem cell and gene therapies or even whole eye transplantation to restore vision is an active area of research, currently mostly advanced using animal models. Overall, biomedical research, including pharmaceutical companies and contract research organizations, use about 100 million mice and 100,000 monkeys every year. Despite this, translation success has remained poor, at ~5-10%. Our long-term goal is to improve the translation probability of INDs that enter clinical trials using functionally viable human donor tissues to improve patient care and reduce animal experiments and suffering. This goal is achieved by developing new technology and assays to test efficacy and safety of INDs preclinically in functionally viable postmortem human donor eyes. Our recent ground-breaking work has demonstrated revival of in vivo-like light signaling in postmortem human retinas. Our central hypothesis is that these human retina samples can be maintained functional for >48-hrs and used efficiently to screen the efficacy of INDs to protect human neurons and glia from stressors caused by retinal and neurodegenerative disease before clinical trials. The rationale for this project is that demonstrating that an IND is not expected to work in human tissue pharmaceutical companies can save >$10M/IND and significant number of animals by preventing those INDs not expected to work in human tissues from advancing to in vivo animal testing or clinical trials. On the other hand, our platform can promote advancement of an IND to the clinical trial and ultimate approval where it could have been otherwise deemed ineffective based on animal experiments, thus, potentially delivering new life- or sight-saving treatments and multi-billion-dollar revenues for pharmaceutical companies. Eyescreen, Inc. will test the central hypothesis in Phase 1 and 2 of this SBIR project. Phase 1 proposes two specific aims. Aim 1: Establish novel ex vivo preclinical models for human ocular diseases; Aim 2: Development of a multichannel drug screening platform in the light-responsive mouse and human retina. These aims will scale up access to viable human eyes by restoring and preserving in vivo-like light responsiveness in eyes procured up to 1-h and stored >48-h post-mortem as well as establish novel new high- throughput platform (Aim 2) for testing impact of INDs on physiology of human retinal neurons and glia exposed to disease stressors like ischemia and inflammation (Aim 1). In Phase 2 Eyescreen Inc., in collaboration with the Vinberg lab, will use these assays to screen clinically approved/failed drugs and compound libraries to test the hypothesis that our platform can improve translation probability. In addition, Phase 2 will expand the utility of our platform to study the impact of not only small-molecule drugs, but also gene therapies, in aged and diseased human eyes.