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 language||English (US)|
|Number of pages||9|
|State||Published - Aug 2012|
Bibliographical noteFunding 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.
- adeno-associated virus
- glucagon-like peptide-1
- hepatocyte growth factor
- type-I diabetes