Abstract
Retinal degenerative diseases (RDDs) affecting photoreceptors (PRs) are one of the most prevalent sources of incurable blindness worldwide. Due to a lack of endogenous repair mechanisms, functional cell replacement of PRs and/or retinal pigmented epithelium (RPE) cells are among the most anticipated approaches for restoring vision in advanced RDD. Human pluripotent stem cell (hPSC) technologies have accelerated development of outer retinal cell therapies as they provide a theoretically unlimited source of donor cells. Human PSC-RPE replacement therapies have progressed rapidly, with several completed and ongoing clinical trials. Although potentially more promising, hPSC-PR replacement therapies are still in their infancy. A first-in-human trial of hPSC-derived neuroretinal transplantation has recently begun, but a number of questions regarding survival, reproducibility, functional integration, and mechanism of action remain. The discovery of biomaterial transfer between donor and PR cells has highlighted the need for rigorous safety and efficacy studies of PR replacement. In this review, we briefly discuss the history of neuroretinal and PR cell transplantation to identify remaining challenges and outline a stepwise approach to address specific pieces of the outer retinal cell replacement puzzle.