Pre-clinical toxicity analysis following subretinal transplantation of an iPSC-derived retinal cell graft in immune suppressed rats.

Abstract

Purpose : Induced pluripotent stem cell (iPSC)-derived retinal progenitor cells are a promising cell type for restoring vision in patients with advanced retinal degeneration. Traditional bolus cell suspension injection often results in poor cell survival and limited synaptic integration following transplantation. To address this problem, we have focused our attention on tissue engineering to reduce post-transplant cell loss while promoting cellular alignment and proper packing density. The purpose of this study was to evaluate local and systemic toxicity following transplantation of human iPSC-derived retinal cell grafts in an immune suppressed rat model.

Methods : Polycaprolactone (PCL) scaffolds were generated by injecting a prepolymer solution into a photopolymerization chamber containing a photomask with 50um spots separated at 25um intervals. Scaffolds were seeded with iPSC-derived retinal progenitor cells generated from 1 of 5 patients. 1mm punches were transplanted into the subretinal space of immune suppressed RNU^-/- rats (N=150) followed by necropsy with complete histopathology, clinical chemistry and hematology performed at 1-, 3-, and 6-months post-transplantation.

Results : Two weeks following scaffold seeding, iPSC-derived retinal precursor cells expressing recoverin and OTX2 were densely packed into vertical columns throughout the scaffold, recapitulating the outer nuclear layer of the retina. Following subretinal transplantation in RNU^-/- rats, retinal reattachment was noted in all eyes. No evidence of treatment induced retinal or systemic toxicity/tumorgenicity was detected by gross or histopathologic evaluation. No significant difference in mean body and/or organ weight was detected between control vs treatment groups at any of the time points evaluated (P>0.05). Finally, no significant treatment induced adverse events were detected via hematology or clinical chemistry (P>0.05).

Conclusions : We successfully developed a high-throughput platform for evaluating local and systemic toxicity following subretinal transplantation of patient derived retinal cell grafts.

This is a 2021 ARVO Annual Meeting abstract.