Lentivirus Mediated Pancreatic Beta-Cell-Specific Insulin Gene Therapy for STZ-Induced Diabetes.
Mol Ther
; 29(1): 149-161, 2021 01 06.
Article
em En
| MEDLINE
| ID: mdl-33130311
ABSTRACT
Autoimmune destruction of pancreatic beta cells is the characteristic feature of type 1 diabetes mellitus. Consequently, both short- and intermediate-acting insulin analogs are under development to compensate for the lack of endogenous insulin gene expression. Basal insulin is continuously released at low levels in response to hepatic glucose output, while post-prandial insulin is secreted in response to hyperglycemia following a meal. As an alternative to multiple daily injections of insulin, glucose-regulated insulin gene expression by gene therapy is under development to better endure postprandial glucose excursions. Controlled transcription and translation of proinsulin, presence of glucose-sensing machinery, prohormone convertase expression, and a regulated secretory pathway are the key features unique to pancreatic beta cells. To take advantage of these hallmarks, we generated a new lentiviral vector (LentiINS) with an insulin promoter driving expression of the proinsulin encoding cDNA to sustain pancreatic beta-cell-specific insulin gene expression. Intraperitoneal delivery of HIV-based LentiINS resulted in the lowering of fasting plasma glucose, improved glucose tolerance and prevented weight loss in streptozoticin (STZ)-induced diabetic Wistar rats. However, the combinatorial use of LentiINS and anti-inflammatory lentiviral vector (LentiVIP) gene therapy was required to increase serum insulin to a level sufficient to suppress non-fasting plasma glucose and diabetes-related inflammation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Lentivirus
/
Diabetes Mellitus Experimental
/
Células Secretoras de Insulina
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Vetores Genéticos
/
Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Ther
Assunto da revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Turquia