Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin

Luca Falqui, Sabina Martinenghi, Giovanni M. Severini, Paola Corbella, M. Vittoria Taglietti, Cinzia Arcelloni, Elena Sarugeri, Lucilla D. Monti, Rita Paroni, Nicoletta Dozio, Guido Pozza, Claudio Bordignon

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Autoimmune destruction of pancreatic β cells in type I, insulin- dependent diabetes mellitus (IDDM) results in the loss of endogenous insulin secretion, which is incompletely replaced by exogenous insulin administration. The functional restoration provided by allogeneic β-cell transplantation is limited by adverse effects of immunosuppression. To pursue an insulin replacement therapy based on autologous, engineered human non-β cells, we generated a retroviral vector encoding a genetically modified human proinsulin, cleavable to insulin in non-β cells, and a human nonfunctional cell surface marker. Here we report that this vector efficiently transduced primary human cells, inducing the synthesis of a modified proinsulin that was processed and released as mature insulin. This retrovirally derived insulin displayed in vitro biological activity, specifically binding to and phosphorylation of the insulin receptor, comparable to human insulin. In vivo, the transplantation of insulin-producing fibroblasts reverted hyperglycemia in a murine model of diabetes, whereas proinsulin-producing cells were ineffective. These results support the possibility of developing insulin production machinery in human non-β cells for gene therapy of IDDM.

Original languageEnglish
Pages (from-to)1753-1762
Number of pages10
JournalHuman Gene Therapy
Volume10
Issue number11
DOIs
Publication statusPublished - Jul 20 1999

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Fibroblasts
Insulin
Proinsulin
Type 1 Diabetes Mellitus
Cell Transplantation
Insulin Receptor
Homologous Transplantation
Cell- and Tissue-Based Therapy
Hyperglycemia
Genetic Therapy
Immunosuppression
Transplantation
Phosphorylation

ASJC Scopus subject areas

  • Genetics

Cite this

Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin. / Falqui, Luca; Martinenghi, Sabina; Severini, Giovanni M.; Corbella, Paola; Taglietti, M. Vittoria; Arcelloni, Cinzia; Sarugeri, Elena; Monti, Lucilla D.; Paroni, Rita; Dozio, Nicoletta; Pozza, Guido; Bordignon, Claudio.

In: Human Gene Therapy, Vol. 10, No. 11, 20.07.1999, p. 1753-1762.

Research output: Contribution to journalArticle

Falqui, L, Martinenghi, S, Severini, GM, Corbella, P, Taglietti, MV, Arcelloni, C, Sarugeri, E, Monti, LD, Paroni, R, Dozio, N, Pozza, G & Bordignon, C 1999, 'Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin', Human Gene Therapy, vol. 10, no. 11, pp. 1753-1762. https://doi.org/10.1089/10430349950017437
Falqui, Luca ; Martinenghi, Sabina ; Severini, Giovanni M. ; Corbella, Paola ; Taglietti, M. Vittoria ; Arcelloni, Cinzia ; Sarugeri, Elena ; Monti, Lucilla D. ; Paroni, Rita ; Dozio, Nicoletta ; Pozza, Guido ; Bordignon, Claudio. / Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin. In: Human Gene Therapy. 1999 ; Vol. 10, No. 11. pp. 1753-1762.
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