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Vladimir Khristov, Arvydas Maminishkis, Balendu Jha, Sheldon S Miller, Kapil Bharti; IND-enabling preclinical toxicity and tumorigenicity studies for AMD-patient’s iPSC-derived RPE in immunocompromised rats. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1991.
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Advanced age-related macular degeneration affects millions of people worldwide and likely initiates because of retinal pigment epithelium (RPE) atrophy. One promising therapeutic approach is to replace atrophied RPE with an autologous iPSC-derived RPE tissue. We have developed and functionally validated an iPSC-derived RPE monolayer tissue grown on a biodegradable poly (lacto-co-glycolic acid) scaffold. The goal of this study is to test toxicity and tumorigenicity of this cell therapy product as part of IND-enabling studies.
AMD patient-specific iPSC-derived RPE were cultured on biodegradable PLGA scaffolds for 5 weeks. Immunocompromised (Crl:NIH-Foxn1rnu) rats were used in these studies to minimize immune response against human cells. Human cells were delivered to the rat subretinal space either as a 5 uL subretinal injection containing 100,000 viable cells, or as a polarized monolayer on PLGA scaffold (0.2 mm2). Throughout the 10-week post-implantation period, rats were monitored for adverse ophthalmic, health, and behavior changes. After sacrifice, rat eyes were evaluated by histology, and rat tissues were tested for the presence of human cells by immunohistochemistry.
Subretinal transplantation of human iPSC-RPE cell suspension or scaffold tissue were well tolerated in the rat model. Although, injection of pure iPSC cell suspension produced teratomas as early as 4 weeks post-implantation, injection of iPSC-RPE cells (human dose) or scaffold transplantation (human equivalent rat dose) did not show any adverse events in a 10-week follow up. Immunostaining for human RPE markers showed clumps of RPE cells in the subretinal space in the case of injections and well-integrated RPE monolayer in the case of iPSC-RPE transplantation.
Use of immunocompromised rat model for safety, toxicity, and tumorigenicity for iPSC-derived RPE testing, has provided reliable and reproducible results using both subretinal injection and implantation studies. The human iPSC-RPE dose was well tolerated in the rat eye. These findings provide strong support towards the safety of iPSC-derived RPE implants for use in humans.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Subretinal dose site 10 weeks after implantation of iPSC-derived RPE on PLGA scaffold immunostained for human cytoplasmic marker STEM121
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