Long-Term Efficacy of GMP Grade Xeno-Free hESC-Derived RPE Cells Following Transplantation

Abstract

PurposeRetinal pigment epithelium (RPE) dysfunction underlies the retinal degenerative process in age-related macular degeneration (AMD), and thus RPE cell replacement provides an optimal treatment target. We characterized longitudinally the efficacy of RPE cells derived under xeno-free conditions from clinical and xeno-free grade human embryonic stem cells (OpRegen) following transplantation into the subretinal space of Royal College of Surgeons (RCS) rats.MethodsPostnatal (P) day 20 to 25 RCS rats (n = 242) received a single subretinal injection of 25,000 (low)-, 100,000 (mid)-, or 200,000 (high)-dose xeno-free RPE cells. BSS+ (balanced salt solution) (vehicle) and unoperated eyes served as controls. Optomotor tracking (OKT) behavior was used to quantify functional efficacy. Histology and immunohistochemistry were used to evaluate photoreceptor rescue and transplanted cell survival at 60, 100, 150, and 200 days of age.ResultsOKT was rescued in a dose-dependent manner. Outer nuclear layer (ONL) was significantly thicker in cell-treated eyes than controls up to P150. Transplanted RPE cells were identified in both the subretinal space and integrated into the host RPE monolayer in animals of all age groups, and often contained internalized photoreceptor outer segments. No pathology was observed.ConclusionsOpRegen RPE cells survived, rescued visual function, preserved rod and cone photoreceptors long-term in the RCS rat. Thus, these data support the use of OpRegen RPE cells for the treatment of human RPE cell disorders including AMD.Translational RelevanceOur novel xeno-free RPE cells minimize concerns of animal derived contaminants while providing a promising prospective therapy to the diseased retina.

Immunological Properties of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells

“…We further explored the immunomodulatory properties of hESC-RPE cells in vivo after subretinal transplantation in RCS rats. Ours and others previous data showed prolonged (19–25 weeks) survival of transplanted functional hESC-RPE cells without evidence of immune cell infiltrates in the area of transplantation in the presence of cyclosporine immunosuppression ( Idelson et al., 2009 , Lu et al., 2009 , McGill et al., 2017 ). In support of the immunomodulatory properties of hESC-RPE cells in vivo , here we further showed their survival and functional rescue after subretinal transplantation in the absence of cyclosporine immunosuppression.…”

“…In line with these results, we previously showed in RCS rats that subretinal transplantation of human fibroblasts was associated with marked inflammatory response despite cyclosporine treatment ( Idelson et al., 2009 ). In contrast, we showed prolonged survival of transplanted hESC-RPE cells that was not associated with inflammatory response in the presence of cyclosporine ( Idelson et al., 2009 , McGill et al., 2017 ). Here we sought to test whether subretinally transplanted RPE cells will survive and function without cyclosporine.…”

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

“…and additional statistics data (individual Hedges' g, lower-and upper limits) can be found in Table S6. Sixteen studies [26][27][28]31,[34][35][36][37][38][39][41][42][43][46][47][48] reporting 96 experiments were included in the meta-analysis. Ninety-one studies were performed in rats and five in mice.…”

Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration

“…Several studies have also examined the tumorigenic risk at the clinical site (Table 1). 10,15,17,27,28,30,51 Analysis of 26 rabbit eyes transplanted with the clinical dose subretinally (50 000 cells in 50uL)…”