Lentivirus Mediated Pancreatic Beta-Cell-Specific Insulin Gene Therapy for STZ-Induced Diabetes

Fulya Erendor, Yunus Emre Eksi, Elif Ozgecan Sahin, Mustafa Kemal Balci, Thomas S. Griffith, Salih Sanlioglu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)149-161
Number of pages13
JournalMolecular Therapy
Volume29
Issue number1
DOIs
StatePublished - Jan 6 2021

Bibliographical note

Funding Information:
This work is supported by the Akdeniz University Scientific Research Administration Division and The Scientific and Technological Research Council of Turkey (TUBITAK) under grant number 215S820 . Special thanks to Dr. Hamit Yasar Ellidag for his technical assistance.

Publisher Copyright:
© 2020 The American Society of Gene and Cell Therapy

Keywords

  • STZ-induced diabetes
  • gene therapy
  • insulin
  • lentivirus
  • pancreas

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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