RT Journal Article SR Electronic T1 Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice JF Science Translational Medicine FD American Association for the Advancement of Science SP eaax9106 DO 10.1126/scitranslmed.aax9106 VO 12 IS 540 A1 Maxwell, Kristina G. A1 Augsornworawat, Punn A1 Velazco-Cruz, Leonardo A1 Kim, Michelle H. A1 Asada, Rie A1 Hogrebe, Nathaniel J. A1 Morikawa, Shuntaro A1 Urano, Fumihiko A1 Millman, Jeffrey R. YR 2020 UL http://stm.sciencemag.org/content/12/540/eaax9106.abstract AB Wolfram syndrome is a recessive genetic disease caused by mutations in WFS1 (Wolfram syndrome 1) and can present with a multitude of symptoms including diabetes, optic atrophy, and neurological problems. There is currently no cure and patients are managed with symptomatic treatment. Maxwell et al. corrected a WFS1 pathogenic variant in patient fibroblast-derived induced pluripotent stem cells (iPSCs) that they then differentiated to pancreatic β cells. The gene-corrected β cells showed improved glucose-stimulated insulin secretion and reversed hyperglycemia for 6 months after their transplantation into diabetic mice. This study may open up the possibility of autologous β cell transplants for patients with Wolfram syndrome.Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to β cells with our recent six-stage differentiation strategy, corrected WS SC-β cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-β cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-β cells that can reverse severe diabetes in an animal model.