Abstract: Transplantation of RPE cells may be of therapeutic benefit in AMD. We developed RPE cells from hESCs using cGMP directed differentiation. Safety and tolerability of these cells is being evaluated in a Phase I/IIa clinical study in patients with dry AMD and geographic atrophy (GA) (NCT02286089). We report accumulated safety and imaging data from subjects in the fully enrolled first 3 cohorts (n=12) and ongoing 4th cohort (n=4). RPE cells in suspension (OpRegen; 50-200k) were subretinally transplanted under local anesthesia to the worse vision eye using either pars plana vitrectomy (PPV) and retinotomy or via an alternative surgical approach utilizing a suprachoroidal route of access. RPE cells ready for onsite thawing and immediate transplantation have also been evaluated. Short course perioperatively systemic immunosuppression is used. Systemic and ocular safety is closely observed, and retinal function and structure are monitored using various imaging modalities. Cohorts 1-3 are in long-term follow-up. Dosing of cohort 4 is ongoing. Treatment has been well tolerated and there have been no unexpected adverse events (AEs) or treatment-related systemic serious AEs. Using PPV, the most common ocular AEs were the formation of predominately mild epiretinal membranes (ERM), though 2 severe ERM were surgically peeled. One PPV-treated patient experienced a retinal detachment of unknown origin. All 3 events were successfully treated. Visual acuity improvement has been noted in all four patients of cohort 4 to date (10-25 letters), which has been maintained for over 15 months in some. In several subjects, within the area of RPE cell transplant, improvements of the ellipsoid zone and RPE layers at the border of GA, as well as directional growth changes in the area of GA, has been seen. Persistent changes observed following treatment include, alterations in drusen appearance, subretinal pigmentation and hyper-reflective areas, suggestive of the presence of transplanted RPE cells. In conclusion, subretinal transplantation of hESC-derived RPE cells in patients with dry AMD and GA appears well tolerated. Imaging findings suggest presence of transplanted cells in the subretinal space. Encouraging structural and clinical changes observed in some patients will require additional follow-up.