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Tytuł pozycji:

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

Tytuł:
Reversal of diabetes in mice by implantation of human fibroblasts genetically engineered to release mature human insulin.
Autorzy:
Falqui L; Telethon Institute for Gene Therapy, Department of Medicine, School of Medicine, University of Milan, Italy. />Martinenghi S
Severini GM
Corbella P
Taglietti MV
Arcelloni C
Sarugeri E
Monti LD
Paroni R
Dozio N
Pozza G
Bordignon C
Źródło:
Human gene therapy [Hum Gene Ther] 1999 Jul 20; Vol. 10 (11), pp. 1753-62.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: New York : M.A. Liebert, c1990-
MeSH Terms:
Cell Transplantation*
Genetic Engineering*
Genetic Vectors*
Diabetes Mellitus, Experimental/*therapy
Fibroblasts/*transplantation
Insulin/*genetics
Proinsulin/*genetics
Animals ; Cell Line ; Fibroblasts/metabolism ; Furin ; Gene Transfer Techniques ; Genetic Therapy ; Humans ; Hyperglycemia/therapy ; Insulin/metabolism ; Insulin Secretion ; Liver/cytology ; Mice ; Mice, Nude ; Moloney murine leukemia virus/genetics ; Muscles/cytology ; Proinsulin/metabolism ; Subtilisins/metabolism
Grant Information:
E.0508 Italy TI_ Telethon; TGT06S01 Italy TI_ Telethon
Substance Nomenclature:
0 (Insulin)
9035-68-1 (Proinsulin)
EC 3.4.21.- (Subtilisins)
EC 3.4.21.75 (Furin)
Entry Date(s):
Date Created: 19990814 Date Completed: 19991028 Latest Revision: 20220129
Update Code:
20240104
DOI:
10.1089/10430349950017437
PMID:
10446915
Czasopismo naukowe
Autoimmune destruction of pancreatic beta 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 beta-cell transplantation is limited by adverse effects of immunosuppression. To pursue an insulin replacement therapy based on autologous, engineered human non-beta cells, we generated a retroviral vector encoding a genetically modified human proinsulin, cleavable to insulin in non-beta 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-beta cells for gene therapy of IDDM.
Comment in: Hum Gene Ther. 1999 Jul 20;10(11):1741-2. (PMID: 10446913)

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