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 language | English |
|---|---|
| Pages (from-to) | 1753-1762 |
| Number of pages | 10 |
| Journal | Human Gene Therapy |
| Volume | 10 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jul 20 1999 |
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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 journal › Article
}
TY - JOUR
T1 - Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin
AU - Falqui, Luca
AU - Martinenghi, Sabina
AU - Severini, Giovanni M.
AU - Corbella, Paola
AU - Taglietti, M. Vittoria
AU - Arcelloni, Cinzia
AU - Sarugeri, Elena
AU - Monti, Lucilla D.
AU - Paroni, Rita
AU - Dozio, Nicoletta
AU - Pozza, Guido
AU - Bordignon, Claudio
PY - 1999/7/20
Y1 - 1999/7/20
N2 - 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.
AB - 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.
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U2 - 10.1089/10430349950017437
DO - 10.1089/10430349950017437
M3 - Article
VL - 10
SP - 1753
EP - 1762
JO - Human Gene Therapy
JF - Human Gene Therapy
SN - 1043-0342
IS - 11
ER -