iPSC-derived retinal organoids: Biological insights and progress toward photoreceptor replacement therapy.

Abstract

Induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) have emerged as a platform for photoreceptor replacement therapy, supported by two complementary approaches: cone precursor cell transplantation and RO transplantation. Both have demonstrated proof of concept for functional synaptic integration with the host retinal network, with the first clinical application of iPSC-derived RO transplantation conducted in 2020. Key mechanistic insights include the role of the host environment in cone integration, genome editing-based enhancement of host-graft synaptogenesis recapitulating developmental synaptic assembly, and synaptic rewiring capacity in the adult primate retina. Beyond biology, successful clinical translation requires establishing meaningful endpoints that reflect stepwise therapeutic improvement, scalable good manufacturing practice (GMP)-compliant manufacturing including validated preservation protocols, and regulatory frameworks accommodating progenitor-stage cell therapies. Together, these advances offer a realistic path toward vision restoration in patients with currently untreatable retinal degenerative diseases.