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Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia

Gene Therapy volume 8, pages 1480–1489 (2001)Cite this article

Abstract

Therapy for type 1 diabetes consists of tight blood glucose (BG) control to minimize complications. Current treatment relies on multiple insulin injections or an insulin pump placement, β-cell or whole pancreas transplantation. All approaches have significant limitations and have led to the realization that novel treatment strategies are needed. Pancreatic acinar cells have features that make them a good target for insulin gene transfer. They are not subject to autoimmune attack, a problem with pancreas or islets transplantation, they are avidly transduced by recombinant adenoviral vectors, and capable of exporting a variety of peptides into the portal circulation. Recombinant adenoviral vectors were engineered to express either wild-type or furin-modified human insulin cDNA (AdCMVhInsM). Immunodeficient mice were made diabetic with streptozotocin and injected intrapancreatically with the vectors. BG and blood insulin levels have normalized after administration of AdCMVhInsM. Immunohistochemistry and electron microscopy showed the presence of insulin in acinar cells throughout the pancreas and localization of insulin molecules to acinar cell vesicles. The data clearly establish a relationship between intrapancreatic vector administration, decreased BG and elevated blood insulin levels. The findings support the use of pancreatic acinar cells to express and secrete insulin into the blood stream. Gene Therapy (2001) 8, 1480–1489.

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Acknowledgements

This work was supported by NIH RO1 DK 54207 (SER) NIH DK 47707 (JMW) and the Juvenile Diabetes Research Foundation. Alberto Auricchio is a recipient of a fellowship (371/B) from Telethon Italia. Technical assistance and advice were provided by the Vector Core and Morphology Core of the Institute for Human Gene Therapy and the RIA core, Diabetes Research Center of the University of Pennsylvania.

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Authors and Affiliations

  1. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    AL Shifrin

  2. Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    A Auricchio & Q-C Yu

  3. Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    J Wilson

  4. Department of Surgery and Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    SE Raper

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Shifrin, A., Auricchio, A., Yu, QC. et al. Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia. Gene Ther 8, 1480–1489 (2001). https://doi.org/10.1038/sj.gt.3301544

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