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Stephen Bravo, Peter Westenskow, Toshihide Kurihara, Alison Dorsey, Liliana Paris, Jonathan Lin, Martin Friedlander; iPS-RPE implantation in the Royal College of Surgeons Rat does not lead to adverse events in a long term study of health and graft stability. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5811.
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Age-related macular degeneration is one of the leading causes of incurable vision loss in industrialized countries and can be caused by retinal pigment epithelium (RPE) dysfunction or death. One exciting potential therapy involves the transplantation of stem cell-derived RPE to replace dysfunctional RPE and maintain photoreceptor function. However, concerns about the abnormal migration, tumor formation, and immunogenicity of stem cell derived treatments have been raised. Several studies, including our own, have shown RPE grafts slow photoreceptor degeneration in animal models of inherited RPE-mediated retinal degeneration, but the long-term safety and health of the animals following transplantation have yet to been examined. Here we present the results of a two-year comprehensive evaluation of the behavior and health of rats implanted with induced pluripotent stem cell (iPS)-derived RPE prepared using an alternative and potentially safer method of reprogramming.
Royal College of Surgeons (RCS) rats received a single subretinal injection of human iPS-derived RPE, PBS, or no injection at three weeks of age (n=30). The animals were continuously immunosuppressed using cyclosporine A. Photoreceptor function was monitored in vivo using optical coherence tomography and focal ERG. All animals were monitored daily and any abnormalities were catalogued. The animals were sacrificed as late as two years post injection and necropsies and blood tests were performed at the end of the study; pathologists also examined select tissues.
iPS-RPE survived in the subretinal space, and no tumors of human origin were observed. Lens and cornea opacities occurred at similar frequencies in both uninjected and injected rats. Unusual extraocular tissue masses developed in all groups, but were observed in a higher frequency in uninjected animals. Necropsies and blood tests revealed no gross abnormalities.
While safety concerns regarding iPS-derived grafts exist, here we show that iPS-RPE grafts are stable and the transplanted cells do not migrate from the eye. Furthermore, they provide photoreceptor rescue in the RCS rat without inducing gross abnormalities in the behavior or health of the host animals. This evidence indicates that implanted iPS-RPE cells do not lead to contraindicative adverse events in an animal model of retinal degeneration.
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