title: Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction.
abstract: Recombinant adeno-associated viruses (rAAVs) have been tested in humans and other large mammals without adverse events. However, one study of mucopolysaccharidosis VII correction in mice showed repeated integration of rAAV in cells from hepatocellular carcinoma (HCC) in the Dlk1-Dio3 locus, suggesting possible insertional mutagenesis. In contrast, another study found no association of rAAV integration with HCC, raising questions about the generality of associations between liver transformation and integration at Dlk1-Dio3. Here we report that in rAAV-treated ornithine transcarbamylase (Otc)-deficient mice, four examples of integration sites in Dlk1-Dio3 could be detected in specimens from liver nodule/tumors, confirming previous studies of rAAV integration in the Dlk1-Dio3 locus in the setting of another murine model of metabolic disease. In one case, the integrated vector was verified to be present at about one copy per cell, consistent with clonal expansion. Another verified integration site in liver nodule/tumor tissue near the Tax1bp1 gene was also detected at about one copy per cell. The Dlk1-Dio3 region has also been implicated in human HCC and so warrants careful monitoring in ongoing human clinical trials with rAAV vectors.
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Nirav
authors.initials: N
authors.lastname: Malani
authors.forename: Mengxin
authors.initials: M
authors.lastname: Li
authors.forename: Troy
authors.initials: T
authors.lastname: Brady
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Li
authors.forename: Haven
authors.initials: H
authors.lastname: Jones
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
mesh_terms: D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000821:virology; D002986:Clinical Trials as Topic; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics; D008099:Liver / Q000473:pathology; D016538:Mucopolysaccharidosis VII / Q000150:complications / Q000235:genetics / Q000628:therapy*; D009954:Ornithine Carbamoyltransferase / Q000187:drug effects / Q000235:genetics / Q000627:therapeutic use*; D016662:Virus Integration / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase; D009954:Ornithine Carbamoyltransferase