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Stem Cell Reports. 2018 Dec 11;11(6):1407-1415. doi: 10.1016/j.stemcr.2018.11.006. Epub 2018 Nov 29.

β Cell Replacement after Gene Editing of a Neonatal Diabetes-Causing Mutation at the Insulin Locus.

Author information

1
Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
2
Salesi Hospital, 60123 Ancona, Italy.
3
Bambino Gesù Children's Hospital, 00164 Rome, Italy.
4
Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: de2220@cumc.columbia.edu.

Abstract

Permanent neonatal diabetes mellitus (PNDM) can be caused by insulin mutations. We generated induced pluripotent stem cells from fibroblasts of a patient with PNDM and undetectable insulin at birth due to a homozygous mutation in the translation start site of the insulin gene. Differentiation of mutant cells resulted in insulin-negative endocrine stem cells expressing MAFA, NKX6.1, and chromogranin A. Correction of the mutation in stem cells and differentiation to pancreatic endocrine cells restored insulin production and insulin secretion to levels comparable to those of wild-type cells. Grafting of corrected cells into mice, followed by ablating mouse β cells using streptozotocin, resulted in normal glucose homeostasis, including at night, and the stem cell-derived grafts adapted insulin secretion to metabolic changes. Our study provides proof of principle for the generation of genetically corrected cells autologous to a patient with non-autoimmune insulin-dependent diabetes. These cases should be readily amenable to autologous cell therapy.

KEYWORDS:

CRISPR/Cas9; cell replacement; gene editing; iPSCs; neonatal diabetes; stem cell-derived β cells

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