From Engraftment to Vision: Defining Evidence of Functional Success in Retinal Cell Replacement Therapy

Abstract

Retinal graft survival and post-treatment visual improvement do not, alone or together, demonstrate functional cell replacement. Apparent benefit may reflect material transfer, trophic rescue, residual host function or procedural and measurement effects. This critical narrative review uses a structured PubMed search covering January 2020 to August 2026, supplemented by seminal studies, to assess retinal pigment epithelium (RPE), photoreceptor, retinal sheet or organoid, and retinal ganglion cell (RGC) transplantation. We separate mechanistic attainment, downstream outcomes and claim-specific causal confidence. Authentic RPE replacement requires donor epithelial function across the host interface, without new synapses. Photoreceptor replacement requires donor phototransduction and transmission to host retinal circuitry; composite grafts additionally require identification of the active donor components. RGC replacement requires both retinal afferent integration and functional reconnection with appropriate central targets. Selected photoreceptor studies demonstrate persuasive local physiological coupling, but durability, donor necessity and generalisability remain incompletely established. Human evidence principally supports feasibility, safety and graft-associated anatomy, rather than convincingly donor-mediated visual restoration. We propose a non-linear evidence framework in which outcomes cannot substitute for secure donor provenance, cell-specific function or host–graft coupling. Spatial concordance, durability, controls, disease-model relevance and experimental unit should qualify every claim.