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

• Published in: Cell reports (Cambridge) Vol. 35; no. 3; p. 109022
• Main Authors: Ribeiro, Joana, Procyk, Christopher A., West, Emma L., O’Hara-Wright, Michelle, Martins, Monica F., Khorasani, Majid Moshtagh, Hare, Aura, Basche, Mark, Fernando, Milan, Goh, Debbie, Jumbo, Neeraj, Rizzi, Matteo, Powell, Kate, Tariq, Menahil, Michaelides, Michel, Bainbridge, James W.B., Smith, Alexander J., Pearson, Rachael A., Gonzalez-Cordero, Anai, Ali, Robin R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2021; Cell Press; Elsevier
• Subjects: Animals; Biomarkers - metabolism; Cell Differentiation; cell therapy; cone photoreceptor; degeneration; Dependovirus - genetics; Dependovirus - metabolism; Disease Models, Animal; electrophysiology; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; macular degeneration; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - pathology; Macular Degeneration - therapy; Male; Mice; Mice, Transgenic; Mycotoxins - genetics; Mycotoxins - metabolism; Organoids - cytology; Organoids - metabolism; Organoids - transplantation; outer segment; Peripherins - genetics; Peripherins - metabolism; Photic Stimulation; Primary Cell Culture; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Receptors, Glutamate - genetics; Receptors, Glutamate - metabolism; Recovery of Function - physiology; rescue; Retinal Bipolar Cells - cytology; Retinal Bipolar Cells - metabolism; Retinal Cone Photoreceptor Cells - cytology; Retinal Cone Photoreceptor Cells - metabolism; Retinal Ganglion Cells - cytology; Retinal Ganglion Cells - metabolism; retinal organoid; Synapses - metabolism; transplantation; Transplantation, Heterologous; Vision, Ocular - physiology; visual function; outer segment; cone photoreceptor; electrophysiology; cell therapy; retinal organoid; transplantation; rescue; degeneration; macular degeneration; visual function
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109022

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. [Display omitted] •Rescue of cone-mediated function by transplantation of purified human cones•Restoration of complex retinal responses and behavior in advanced degeneration•Formation of human-murine putative synaptic connections•Relevant controls exclude material transfer and trophic support Cone photoreceptor death and associated central vision loss are common to many retinal dystrophies. Ribeiro et al. show that transplantation of purified human pluripotent stem cell-derived cones into a mouse model of end-stage disease allows the formation of functional connections with the underlying retina and restores cone-mediated visual function.