Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors
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
Affiliations
Joana Ribeiro
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Christopher A. Procyk
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Emma L. West
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Michelle O’Hara-Wright
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Monica F. Martins
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Majid Moshtagh Khorasani
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Aura Hare
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Mark Basche
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Milan Fernando
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Debbie Goh
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Neeraj Jumbo
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Matteo Rizzi
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Kate Powell
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Menahil Tariq
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Michel Michaelides
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
James W.B. Bainbridge
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Alexander J. Smith
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Rachael A. Pearson
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Anai Gonzalez-Cordero
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
Robin R. Ali
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Kellogg Eye Centre, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA; Corresponding author
Summary: 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.
