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.