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  • Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

Cell reports (2021-04-22)
Joana Ribeiro, Christopher A Procyk, Emma L West, Michelle O'Hara-Wright, Monica F Martins, Majid Moshtagh Khorasani, Aura Hare, Mark Basche, Milan Fernando, Debbie Goh, Neeraj Jumbo, Matteo Rizzi, Kate Powell, Menahil Tariq, Michel Michaelides, James W B Bainbridge, Alexander J Smith, Rachael A Pearson, Anai Gonzalez-Cordero, Robin R Ali
ABSTRACT

Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium bicarbonate, ACS reagent, ≥99.7%
Sigma-Aldrich
D(−)-2-Amino-5-phosphonopentanoic acid, NMDA receptor antagonist
Sigma-Aldrich
DNQX, ≥98% (TLC)
Sigma-Aldrich
Ames′ Medium, With L-glutamine, without sodium bicarbonate, powder, suitable for cell culture
Sigma-Aldrich
Anti-Vesicular Glutamate Transporter 1 Antibody, serum, Chemicon®
Sigma-Aldrich
Anti-Nuclei Antibody, clone 235-1, clone 235-1, Chemicon®, from mouse