The goal of this project is to develop a cell-based therapy as a durable sub-retinal transplant to benefit patients with dry age-related macular degeneration (AMD). We recently discovered a novel adult retinal pigment epithelial stem cell, the RPESC, in the human RPE layer that self-renews and produces highly pure populations of RPE progeny (RPESC-RPE). In collaboration with NEI researchers, we have shown that RPESC-RPE recapitulate key functions of native RPE, including polarized cytokine secretion, fluid transport and phagocytosis of rod outer segments, critical for photoreceptor cell survival and retinal health. With the U. Rochester GMP facility (USCGF), we have developed a robust, reproducible cGMP manufacturing process. Each RPESC line is isolated from donated globes using material that would otherwise be discarded after cornea collection. There is no shortage of starting material as c.100,000 globes/year are donated to US eye banks with CLIA-certified FDA-compliant donor testing. RPESCs isolated from a single donor can produce 5x108 RPESC-RPE progeny after only 2 passages. The RPESC-RPE product is simple to manufacture, and the low-cost to produce multiple master cell banks (MCBs) makes HLA matching to patients feasible in the future. Following FDA guidance, we have produced a clinical grade MCB and performed pre-clinical IND- enabling studies that indicate a favorable safety profile with no tumor detection or toxicity reported. Using two different rat models, we demonstrated long-term engraftment into the RPE layer and significant vision rescue in the Royal College of Surgeons (RCS) rat, a model previously validated for cell transplant IND-enabling studies for AMD. We found that subretinal transplantation of adult RPESC-derived RPE at an intermediate stage of differentiation increases vision rescue in the RCS rat, while earlier or later stage cells were significantly less efficacious. Our studies of this efficacious stage have enabled identification of candidate potency markers. The goals of this Regenerative Medicine Innovation Project (RMIP) Investigator-initiated RFA-HL-18-030 application are to: 1. Advance CMC for the RPESC-RPE cell product in collaboration with the RM Innovation catalyst in anticipation of clinical trial and RMAT application; 2. Complete ongoing histology studies that address transplanted cell function and integration and persistence in vivo, and 3. Complete and submit the IND application and prepare for a Phase I/IIa phase clinical trial. Much progress has been made to complete each of these aims, including IND-enabling safety and efficacy studies, which makes the proposed timeline and budget feasible. The proposed clinical trial to transplant RPESC-RPE subretinally as a suspension uses established vitreoretinal surgical techniques to minimize retinotomy size and surgical complications. Clinical trial teams at the University of Michigan Kellogg Eye Center and the Stanford University Byers Eye Institute include surgeons experienced with stem cell products and AMD patients. Our goal is to improve daily living for the large number of AMD patients who currently lack therapeutic options for their progressive vision loss.
Stem cell-derived retinal pigment epithelial cell transplantation to treat age-related macular degeneration is an active area of investigation. For this purpose, we utilize a novel adult RPE stem cell normally present in the eye. Definitive safety, efficacy and manufacturing studies are complete with positive results. We now aim to complete analyses of the safety and efficacy data, introduce a new cell characterization marker, finalize an investigational new drug application for submission to the FDA and prepare clinical trial sites.
