Phase1/2a Clinical Trial of RPESC-derived RPE Transplantation as Therapy for Non-exudative Age-related Macular Degeneration

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Project Summary/Abstract Age-related macular degeneration (AMD) is a major cause of blindness in our aging population. Early AMD pathogenesis involves atrophy of the retinal pigment epithelium (RPE) with accompanying loss of retinal function and vision. Although therapy is available for exudative (wet) AMD, an effective treatment is not available for the more common non- exudative (dry) AMD form. Pluripotent stem cell (PSC)-derived RPE (PSC-RPE) transplantation has shown promise for AMD in early clinical trials. Due to the highly proliferative and plastic nature of PSC, however, extensive differentiation to RPE is needed prior to transplantation to avoid tumor growth and genotype instability inherent to the PSC source. We discovered an adult RPE stem cell (RPESC) with restricted proliferative and lineage potential. RPESC-derived RPE (RPESC- RPE) do not form tumor enabling transplantation of less differentiated RPE at the progenitor stage. We found that transplanted RPE progenitor cells were more effective than highly differentiated progeny at vision rescue in the Royal College of Surgeons rat model of AMD. RPESC-RPE differentiated for 4 weeks into an intermediate RPE progenitor stage rescued vision more effectively than cells differentiated for 8 weeks into the mature RPE phenotype. This improved efficacy combined with lack of tumorgenicity provides compelling rationale for the proposed Phase 1/2a clinical trial of RPESC-RPE transplantation as therapy for dry AMD. Experienced clinical trial teams have been assembled at the University of Michigan Kellogg Eye Center (KEC) and Stanford University. The KEC team includes a vitreoretinal surgeon experienced in stem cell research who will recruit, perform interventions, and manage participant care. Another retinal specialist will direct post-intervention assessment at the KEC Clinical Research Center, and a senior KEC retinal specialist will serve as on-site medical monitor. A clinical trialist highly experienced in early phase ophthalmic trials will provide regulatory, design and statistical support. The Neural Stem Cell Institute (NSCI) and the Stanford University Byers Eye Institute will work with KEC to provide scientific and clinical guidance for the proposed trial. Single cell transcriptomic analyses generated at NSCI will be correlated with clinical outcomes, which will contribute to the recognized need for improved cell product identity and potency measures in regenerative medicine generally. We propose to combine a strong program in stem cell biology with an experienced team in the conduct of ophthalmic clinical trials Sound clinical trial conduct aims to produce reliable outcomes results to evaluate RPESC-RPE progenitor cell transplantation as therapy for dry AMD. Outcomes will be correlated with product identity and potency measures at the single cell level. Completion of the proposed work will improve understanding of RM product characterization and advance a unique type of adult stem cell to replace RPE for dry AMD patient benefit.