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Mol Ther Methods Clin Dev. 2017 Sep 30;8:8-20. doi: 10.1016/j.omtm.2017.09.006. eCollection 2018 Mar 16.

Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice.

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Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA.
Department of Pathology, IUSM, Indianapolis, IN 46202, USA.
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Dimension Therapeutics, Cambridge, MA 02139, USA.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN 46202, USA.
Pancreatic Cancer Signature Center, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN 43202, USA.
Department of Medicine, IUSM, Indianapolis, IN 43202, USA.


Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg). Intraductal delivery of 1 × 1011 vg scAAV6.GFP transduced acini, ductal cells, and islet cells with >50%, ∼48%, and >80% efficiency, respectively, and >80% pancreatic transduction was achieved with 5 × 1011 vg. In a KrasG12D-driven pancreatic cancer mouse model, intraductal delivery of scAAV6.GFP targeted acini, epithelial, and stromal cells and exhibited persistent gene expression 5 months post-delivery. In normal mice, intraductal delivery induced a transient increase in serum amylase/lipase that resolved within a day of infusion with no sustained pancreatic inflammation or fibrosis. Similarly, in PDAC mice, intraductal delivery did not increase pancreatic intraepithelial neoplasia progression/fibrosis. Our study demonstrates that scAAV6 targets the pancreas/neoplasm efficiently and safely via retrograde pancreatic intraductal delivery.


AAV; AAV6; ERCP; PDAC; gene therapy; intraductal; pancreatic cancer and pancreatitis; retrograde pancreatic gene delivery; targeted gene delivery

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