Project Grant R01EY035092

CELL-BASED THERAPIES FOR RETINAL DEGENERATION - PROJECT SUMMARY/ABSTRACT THIS PROJECT ADDRESSES THE NEI AUDACIOUS GOAL INITIATIVE (AGI) OF RESTORING VISION THROUGH REGENERATION OF PHOTORECEPTOR CELLS AND THEIR CONNECTIONS. AMONG DEGENERATIVE DISEASES OF THE OUTER RETINA AMENABLE TO REGENERATIVE THERAPIES, DRY AGE-RELATED MACULAR DEGENERATION (AMD) IS A MAJOR TARGET. AMD IS THE LEADING CAUSE OF IRREVERSIBLE BLINDNESS IN DEVELOPED COUNTRIES, WITH THE DRY FORM ACCOUNTING FOR NEARLY 90% OF PATIENTS AFFECTED BY THIS CONDITION. PATIENTS WITH END-STAGE DRY-AMD PRESENT MACULAR PHOTORECEPTOR AND RETINAL PIGMENT EPITHELIUM (RPE) ATROPHY, AND THERE IS NO AVAILABLE TREATMENT THAT CAN RESTORE THEIR LOST VISION. TO ADDRESS THIS IMPORTANT UNMET NEED WE NEED TO ADDRESS TWO CRITICAL GAPS: DEVISING NOVEL CELL-BASED TRANSPLANTATION STRATEGIES TO JOINTLY REGENERATE PHOTORECEPTOR AND RPE CELLS, AND IDENTIFYING MECHANISMS SUPPORTING STRUCTURAL AND FUNCTIONAL INTEGRATION OF THE TRANSPLANTED CELLS. THE GOAL OF THIS PROJECT IS TO DIRECTLY ADDRESS THESE TWO CRITICAL GAPS BY ESTABLISHING FEASIBILITY AND MECHANISMS OF STRUCTURAL AND FUNCTIONAL INTEGRATION OF A NOVEL STEM CELL-DERIVED 3D RETINAL TRANSPLANT CONTAINING PHOTORECEPTORS AND RPE (3DNR/RPE) IN A MINIPIG MODEL OF END- STAGE MACULAR ATROPHY. OUR PRELIMINARY RESULTS SHOWED SURVIVAL OF OUR 3DNR/RPE TRANSPLANTS WITHIN THE SUBRETINAL SPACE OF OUR MINIPIG MODEL. THIS WAS ACCOMPANIED BY INCREASED LIGHT RESPONSE SIX WEEKS POST- TRANSPLANTATION. THESE RESULTS STRONGLY SUPPORT OUR OVERARCHING HYPOTHESIS: THAT HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSC)-DERIVED 3DNR/RPE TRANSPLANTS ACHIEVE STRUCTURAL AND FUNCTIONAL INTEGRATION. IN THESE STUDIES, WE WILL USE AN ARRAY OF COMPLEMENTARY MULTIMODAL IN VIVO OCULAR EVALUATION, EX VIVO ASSESSMENTS, AND NON-INVASIVE IN VIVO FUNCTIONAL IMAGINING TO DETERMINE THE EXTENT OF STRUCTURAL AND FUNCTIONAL INTEGRATION OF OUR HIPSC-DERIVED 3DNR/RPE TRANSPLANTS. WE WILL SPECIFICALLY TEST THE FOLLOWING HYPOTHESES: I) CO-TRANSPLANTED PHOTORECEPTORS AND RPE RE-ESTABLISH PHYSIOLOGICAL AND FUNCTIONAL INTERACTIONS; II) TRANSPLANTED PHOTORECEPTORS SYNAPSE WITH BOTH, CO-TRANSPLANTED AND HOST BIPOLAR CELLS, WHICH IN TURN COMMUNICATE WITH HOST AMACRINE AND/OR GANGLION CELLS; III) 3DNR/RPE TRANSPLANTS LEAD TO INCREASED LIGHT RESPONSE FROM ALL PHOTORECEPTOR CELL TYPES; AND IV) 3DNR/RPE TRANSPLANTS LEAD TO LIGHT-TRIGGERED RESPONSE IN BIPOLAR AND GANGLION CELLS. THIS IS A HIGHLY INNOVATIVE STRATEGY GROUNDED IN OUR ABILITY TO GENERATE RETINAL TISSUE TRANSPLANTS DERIVED FROM HIPSC THAT CONTAIN FUNCTIONAL LIGHT-SENSITIVE PHOTORECEPTORS AND RPE CELLS ORGANIZED AS IN THE NATIVE RETINA. USE OF NOVEL HIGH-RESOLUTION TECHNOLOGY FOR NON-INVASIVE FUNCTIONAL ASSESSMENT OF TRANSPLANT INTEGRATION IS AN ADDITIONAL INNOVATIVE ASPECT OF OUR PROPOSED STUDIES. THE POTENTIAL IMPACT OF OUR STUDIES IS HIGHLY SIGNIFICANT AS IT COULD LEAD TO CRITICAL PRECLINICAL EVIDENCE SUPPORTING THE FEASIBILITY OF HIPSC-DERIVED 3DNR/RPE TRANSPLANTS FOR CELL- REPLACEMENT THERAPY. IN TURN, THIS TRANSPLANT STRATEGY COULD BECOME THE FIRST AVAILABLE SOLUTION FOR RESTORING VISION IN PATIENTS AFFECTED BY END-STAGE DRY-AMD.