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 chromograninA. 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 b 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.

Ma, S., Viola, R., Sui, L., Cherubini, V., Barbetti, F., & Egli, D. (2018). b Cell Replacement after Gene Editing of a Neonatal Diabetes-Causing Mutation at the Insulin Locus. STEM CELL REPORTS [10.1016/j.stemcr.2018.11.006].

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

Barbetti Fabrizio;
2018-11-06

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 chromograninA. 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 b 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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/13 - Endocrinologia
eng
Con Impact Factor ISI
Ma, S., Viola, R., Sui, L., Cherubini, V., Barbetti, F., & Egli, D. (2018). b Cell Replacement after Gene Editing of a Neonatal Diabetes-Causing Mutation at the Insulin Locus. STEM CELL REPORTS [10.1016/j.stemcr.2018.11.006].
Ma, S; Viola, R; Sui, L; Cherubini, V; Barbetti, F; Egli, D
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
ATG INS mut.pdf

accesso aperto

Licenza: Copyright dell'editore
Dimensione 2.04 MB
Formato Adobe PDF
2.04 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/208512
Citazioni
  • ???jsp.display-item.citation.pmc??? 24
  • Scopus 33
  • ???jsp.display-item.citation.isi??? 38
social impact