Human cone photoreceptor transplantation stimulates remodeling and restores function in AIPL1 model of end-stage Leber congenital amaurosis
Summary
Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1-/- model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
| Authors | Procyk CA, Melati A, Ribeiro J, Liu J, Branch MJ, Delicata JD, Tariq M, Kalarygrou AA, Kapadia J, Khorsani MM, West EL, Smith AJ, Gonzalez-Cordero A, Ali RR, Pearson RA |
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| Journal | Stem cell reports |
| Publication Date | 2025 Apr 8;20(4):102470 |
| PubMed | 40154478 |
| PubMed Central | PMC12069896 |
| DOI | 10.1016/j.stemcr.2025.102470 |