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

Shuangyu Ma, Ryan Viola, Lina Sui, Valentino Cherubini, Fabrizio Barbetti, Dieter Egli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Number of pages8
JournalStem Cell Reports
DOIs
Publication statusE-pub ahead of print - Nov 20 2018

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