dsAAV8-mediated gene transfer and beta-cell expression of IL-4 and beta-cell growth factors are capable of reversing early-onset diabetes in NOD mice

作者：Gaddy D F; Riedel M J; Bertera S; Kieffer T J; Robbins P D^*

来源：Gene Therapy, 2012, 19(8): 791-799.

DOI：10.1038/gt.2011.181

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

Type-I diabetes is a chronic disease mediated by autoimmune destruction of insulin-producing beta-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 beta-cells of interleukin (IL)-4 in combination with beta-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 beta-cell proliferation and survival in vivo, significantly delaying diabetes progression in NOD mice, and reversing disease in similar to 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 beta-cells of immunomodulatory factors and beta-cell growth factors.

• 出版日期2012-8