Regenerative therapies using pluripotent stem cell-derived retinal organoids

Abstract Photoreceptor degeneration leads to irreversible vision loss in numerous inherited retinal diseases. While gene therapy addresses specific mutations, cell replacement strategies offer a potentially broader solution applicable across multiple genetic causes. This review traces the evolution of retinal transplantation approaches, from early fetal tissue transplants to modern pluripotent stem cell-derived retinal organoids. The development of three-dimensional retinal organoids marked a significant advancement, providing transplantable tissue that maintains cellular architecture and relationships. Preclinical studies have demonstrated that transplanted organoids can develop mature photoreceptors with outer segments, form synaptic connections with host bipolar cells, restore light responsiveness in host retinal ganglion cells, and enable light-responsive behaviors in animal models. The first human clinical application using induced pluripotent stem cell-derived retinal organoids has demonstrated safety and stable graft survival over 2 years, with potential functional improvement in one patient at around 1 year after transplantation. Recent innovations include genome-edited retinal organoids with reduced competing bipolar cells, which enhance functional integration by increasing host-graft connectivity. While significant challenges remain, including increasing transplantation area, improving surgical techniques, optimizing patient selection, and addressing manufacturing and regulatory considerations, continued progress in this field may offer hope for some visual improvement in currently untreatable retinal degenerative conditions.