title: No evidence for tumorigenesis of AAV vectors in a large-scale study in mice.
abstract: Six hundred ninety-five mice received adeno-associated virus (AAV) vectors, mostly via portal vein injection. At necropsy, the livers were inspected for tumors, and tissue sections were prepared for histology. We observed only one tumor, a lipoma, resulting in a tumor frequency of 0.14%. This tumor contained fewer vector genomes per total DNA than the surrounding liver tissue, as shown by quantitative PCR. In another mouse we found a macroscopically visible nodule containing lymphocytes. Immunohistochemistry revealed cells not of monoclonal origin, and they contained fewer AAV genomes than the surrounding hepatocytes. There were no macroscopic tumors in 226 control mice. Upon microscopic examination, lymphocytic infiltrates were found in 5% of livers of both control and vector-treated mice; no transgene expression was seen in those infiltrates in AAV-injected animals. Compared to an average frequency of spontaneous liver tumors in C57BL/6 mice (0-10%), and given the absence of high levels of vector DNA in the observed tumor, we conclude that AAV vectors do not predispose these target animals to the formation of liver tumors.
authors.affiliation: Gene Therapy Program, Division of Medical Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Corinna
authors.initials: C
authors.lastname: Lebherz
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Flieder
authors.forename: Mark S
authors.initials: MS
authors.lastname: Bove
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Guang Ping
authors.initials: GP
authors.lastname: Gao
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Nelson A
authors.initials: NA
authors.lastname: Wivel
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D019076:Transgenes