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

• Published in: Molecular therapy. Methods & clinical development Vol. 8; no. C; pp. 8 - 20
• Main Authors: Quirin, Kayla A, Kwon, Jason J, Alioufi, Arafat, Factora, Tricia, Temm, Constance J, Jacobsen, Max, Sandusky, George E, Shontz, Kim, Chicoine, Louis G, Clark, K Reed, Mendell, Joshua T, Korc, Murray, Kota, Janaiah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 16-03-2018; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; AAV6; Catheters; Deoxyribonucleic acid; DNA; Efficiency; ERCP; Fibrosis; Gene expression; gene therapy; Gene transfer; Genomes; intraductal; Islet cells; Laboratory animals; Lipase; Medical prognosis; Mutation; Neoplasia; Pancreatic cancer; pancreatic cancer and pancreatitis; Pancreatitis; PDAC; retrograde pancreatic gene delivery; Safety; Serotypes; Statistical analysis; Stromal cells; targeted gene delivery; Tumors; Vectors (Biology); pancreatic cancer and pancreatitis; targeted gene delivery; PDAC; AAV; gene therapy; ERCP; AAV6; intraductal; retrograde pancreatic gene delivery
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2017.09.006

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 × 10
viral genomes (vg). Intraductal delivery of 1 × 10
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 × 10
vg. In a Kras
-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.