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Retinal pigment epithelium (RPE) cells perform a variety of roles that are principally directed at maintaining retinal function and homeostasis and their loss causes conditions such as age-related macular degeneration (AMD) and Stargardt disease (STGD). Regeneration of the loss or dystrophic RPE cells with stem cell-derived RPE may provide a potential therapeutic option. STGD is the commonest form of juvenile-onset, inherited macular degeneration. In order to determine the safety and efficacy of embryonic stem (ES) cell-derived RPE transplantation for the treatment of STGD, twelve subjects with STGD received a suspension of hES-derived RPE cells in escalating dose cohorts. Following the intervention, areas of sub retinal pigmentation were noted in all participants, suggestive of engraftment and survival. Transplanted hES-derived RPE cells were often observed overlying regions of atrophic Bruch's membrane (BrM). There was no evidence of tumorigenicity, immune adverse events or other serious safety concerns related to the transplanted cells. Furthermore, there was no significant change in visual function in the study eye of any participant. In order to improve the efficacy of ES-derived RPE transplantation, I developed an improved rodent model of retinal degeneration that features focal regions of atrophic BrM. I used a diode laser to selectively ablate RPE and observed focal regions of RPE atrophy with corresponding changes in choroidal vasculature that resemble those observed in retinal degenerative disease. Moreover, transplantation of human ES- and human induced pluripotent stem cell (iPS)-derived RPE resulted in re-population and restoration of RPE morphology post ablation. Although transplanted ES-derived RPE survived well on healthy BrM, attachment and survival of RPE is compromised on BrM that exhibits AMD or senescent changes. A potential strategy to promote survival and engraftment where there is damaged BrM is to deliver ES-derived RPE on a carrier substrate. I used a bespoke electrospun scaffold consisting of poly(e-caprolactone) and seeded this with either hESC or hiPSC-derived RPE. Transplantation of ES-derived RPE resulted in a functional monolayer of RPE with correct orientation and polarity on a biodegradable, porous and biocompatible membrane. These studies support further work in large animal models using ES-derived RPE scaffolds to restore the RPE in the presence of a compromised BrM.