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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

Gene Therapy volume 19, pages 791–799 (2012)Cite this article

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    D F Gaddy & P D Robbins

  2. Departments of Cellular and Physiological Sciences and Surgery, Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada

    M J Riedel & T J Kieffer

  3. Rangos Research Center, Diabetes Research Institute, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    S Bertera

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  1. D F Gaddy
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  2. M J Riedel
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  3. S Bertera
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  4. T J Kieffer
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  5. P D Robbins
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Correspondence to P D Robbins.

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Competing interests

Dr Kieffer is a founder of Engene Inc., which is developing non-viral gene delivery methods to the gut for treatment of T1D. Dr Robbins is a member of the SAB for Engene.

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Gaddy, D., Riedel, M., Bertera, S. et al. 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. Gene Ther 19, 791–799 (2012). https://doi.org/10.1038/gt.2011.181

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