Production of clinical grade patient iPSC-derived 3D retinal organoids containing transplantable photoreceptor cells

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Abstract Neurodegenerative conditions that affect the retina are currently the leading cause of incurable blindness in the developed world. Although gene and drug therapies are being developed to slow disease progression in some cases, restorative cell replacement approaches are needed for patients with significant vision impairment due to retinal degeneration. While a variety of different cell types have been evaluated in the context of retinal cell replacement, induced pluripotent stem cells (iPSCs), which can be generated and delivered as an autologous therapeutic, are in many ways the most attractive donor cell source currently available. Like embryonic stem cells, iPSCs must be differentiated into the target therapeutic cell type prior to transplantation. For instance, for patients with retinitis pigmentosa who have primary photoreceptor cell disease, photoreceptor cell derivation and enrichment are required prior to transplantation. Although other effective retinal differentiation protocols exist, they are often not fully compatible with clinical manufacturing. In this study, we report development of a xeno-free 3D retinal differentiation protocol based on the most robust adherent/non-adherent 3D differentiation strategies published to date. In addition, we demonstrate that while iPSC reprogramming efficiency is enhanced under reduced oxygen tension (i.e., 5%), efficient embryoid body and subsequent retinal organoid production require standard oxygen levels (i.e., 21%). Finally, we show that photoreceptor precursor cells obtained from 3D retinal organoids derived using the developed protocol under current good manufacturing practices (cGMP) survive in the subretinal space of dystrophic Pde6b -null rats for 1-month post-transplantation and form new synaptic connections with host bipolar neurons. Significance statement In this study, we report development of a xeno-free, cGMP compliant iPSC-3D retinal differentiation protocol for production of transplantable photoreceptor precursor cells.

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