DsAAV8-mediated gene transfer and Β-cell expression of IL-4 and Β-cell growth factors are capable of reversing early-onset diabetes in NOD mice

D. F. Gaddy, M. J. Riedel, S. Bertera, T. J. Kieffer, P. D. Robbins

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Type-I diabetes is a chronic disease mediated by autoimmune destruction of insulin-producing β-cells. Although progress has been made towards improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Here, we examined whether double-stranded adeno-associated virus serotype 8 (dsAAV8)-mediated gene delivery to endogenous Β-cells of interleukin (IL)-4 in combination with Β-cell growth factors can reverse early-onset diabetes in NOD mice. Our results demonstrate that a single treatment with dsAAV8 vectors expressing IL-4 in combination with glucagon-like peptide-1 or hepatocyte growth factor/NK1 under the regulation of the insulin promoter enhanced Β-cell proliferation and survival in vivo, significantly delaying diabetes progression in NOD mice, and reversing disease in 10% of treated NOD mice. These results demonstrate the ability to reverse hyperglycemia in NOD mice with established diabetes by in vivo gene transfer to Β-cells of immunomodulatory factors and β-cell growth factors.

Original languageEnglish (US)
Pages (from-to)791-799
Number of pages9
JournalGene therapy
Volume19
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by a program grant from the Juvenile Diabetes Research Foundation (JDRF) to PDR, and DFG was supported by a fellowship from the JDRF. MJR was supported by the Michael Smith Foundation for Health Research (MSFHR), the Canadian Diabetes Association, the Stem Cell Network and the JDRF. TJK is a MSFHR senior scholar. We thank Maliha Zahid (University of Pittsburgh) for assistance with statistical analysis and Joan Nash (University of Pittsburgh) for assistance with microscopy analysis.

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • adeno-associated virus
  • glucagon-like peptide-1
  • hepatocyte growth factor
  • interleukin-4
  • type-I diabetes

Fingerprint Dive into the research topics of 'DsAAV8-mediated gene transfer and Β-cell expression of IL-4 and Β-cell growth factors are capable of reversing early-onset diabetes in NOD mice'. Together they form a unique fingerprint.

Cite this