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Widespread and Stable Pancreatic Gene Transfer by Adeno-Associated Virus Vectors via Different Routes

¹ Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
³ Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
⁴ Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Xiao Xiao, PhD, Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Room E1644 BST, Pittsburgh, PA 15261. E-mail: xiaox{at}pitt.edu

Abbreviations: AAV, adeno-associated virus; CB, cytomegalovirus enhancer/chicken ß-actin promoter; dsAAV, double-stranded AAV; GFP, green fluorescent protein; H-E, hemotoxilin-eosin; mIP, mouse insulin promoter; ssAAV, single-stranded AAV

Diabetes is a disease of epidemic proportions and is on the rise worldwide. Gene therapy has been actively pursued but limited by technical hurdles and profound inefficiency of direct gene transfer to the pancreas in vivo. Here, we show that, for the first time, appropriate serotypes of adeno-associated virus (AAV), coupled with a double-stranded vector DNA cassette, enable extensive and long-term in vivo gene transfer in the adult mouse pancreas by three different delivery methods. Intraperitoneal and intravenous delivery of AAV8 effectively transduced exocrine acinar cells as well as endocrine ß-cells, while local pancreatic intraductal delivery of AAV6 showed the best efficiency in the ß-cells among all AAV serotypes tested in this study. Nearly the entire islet population showed gene transfer but with distinct gene transfer efficiency and patterns when different delivery methods and vectors were used. Importantly, localized gene delivery coupled with an insulin promoter allowed extensive yet specific gene expression in the ß-cells. These effective new methods should provide useful tools to study diabetes pathogenesis and gene therapy.

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