Hereditary retinal dystrophies (HRD) represent a significant cause of blindness, affecting mostly retinal pigment epithelium (RPE) and photoreceptors (PRs), and currently suffer from a lack of effective treatments. Highly specialized RPE and PR cells interact mutually in the functional retina, therefore primary HRD affecting one cell type leading to a secondary HRD in the other cells. Phagocytosis is one of the primary functions of the RPE and studies have discovered that mutations in the phagocytosis-associated gene Mer tyrosine kinase receptor (MERTK) lead to primary RPE dystrophy. Treatment strategies for this rare disease include the replacement of diseased RPE with healthy autologous RPE to prevent PR degeneration. The generation and directed differentiation of patient-derived human-induced pluripotent stem cells (hiPSCs) may provide a means to generate autologous therapeutically-relevant adult cells, including RPE and PR. However, the continued presence of the MERTK gene mutation in patient-derived hiPSCs represents a significant drawback. Recently, we reported the generation of a hiPSC model of MERTK-associated Retinitis Pigmentosa (RP) that recapitulates disease phenotype and the subsequent creation of gene-corrected RP-hiPSCs using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9. In this study, we differentiated gene-corrected RP-hiPSCs into RPE and found that these cells had recovered both wild-type MERTK protein expression and the lost phagocytosis of fluorescently-labeled photoreceptor outer segments observed in uncorrected RP-hiPSC-RPE. These findings provide proof-of-principle for the utility of gene-corrected hiPSCs as an unlimited cell source for personalized cell therapy of rare vision disorders.

Center for Biomedical Network Research on Rare Diseases ISCIII 28040 Madrid Spain

Department of Genetics and Genomics IIS Fundación Jiménez Díaz 28040 Madrid Spain

Institute of Experimental Medicine Department of Neuroregeneration Czech Academy of Science 14220 Prague Czech Republic

Metabolic Research Laboratories Wellcome Trust MRC Institute of Metabolic Science University of Cambridge Addenbrooke's Hospital Cambridge CB2 0QQ UK

National Stem Cell Bank Valencia Node Proteomics Genotyping and Cell Line Platform PRB3 ISCIII Research Centre Principe Felipe c Eduardo Primo Yúfera 3 46012 Valencia Spain

Stem Cells Therapies in Neurodegenerative Diseases Lab Centro de Investigación Principe Felipe 46012 Valencia Spain

Wellcome Sanger Institute Wellcome Genome Campus Hinxton Cambridge CB10 1SA UK

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