Long-Term Safety and Function of RPE from Human Embryonic Stem Cells in Preclinical Models of Macular Degeneration

TLDR

Long‑term safety and efficacy assessments are essential before human embryonic stem cell (hESC) therapies can enter clinical use, particularly for retinal pigment epithelium (RPE) replacement in age‑related macular degeneration and Stargardt disease. The study aimed to address safety concerns of hESC‑derived RPE by conducting a Good Laboratory Practice‑compliant investigation. The investigation involved subretinal transplantation of GMP‑compliant hESC‑RPE into NIH III immune‑deficient mice under Good Laboratory Practice conditions. Long‑term studies in RCS rats and Elov14 mice showed that hESC‑derived RPE survived >220 days, preserved photoreceptor integrity and visual function dose‑dependently, produced near‑normal retinal performance, and produced no teratoma or tumor formation, supporting their safety and efficacy as a renewable RPE source. Potential conflicts of interest are disclosed at the end of the article.

Abstract

Abstract Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.