UMass Chan Medical School Faculty Publications

UMMS Affiliation

Gene Therapy Center; Department of Microbiology and Physiologcal Systems; Department of Pediatrics

Publication Date


Document Type



Dependovirus; Genetic Vectors; Gene Therapy; Carcinoma, Hepatocellular


Biomedical Engineering and Bioengineering | Medical Genetics | Medical Immunology


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.


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This is a copy of an article published in Human Gene Therapy © 2013 copyright Mary Ann Liebert, Inc.; Human Gene Therapy is available online at: Publisher PDF posted as allowed by the publisher's author rights policy at

DOI of Published Version



Li Zhong, Nirav Malani, Mengxin Li, Troy Brady, Jun Xie, Peter Bell, Shaoyong Li, Haven Jones, James M. Wilson, Terence R. Flotte, Frederic D. Bushman, and Guangping Gao. Human Gene Therapy. May 2013, 24(5): 520-525. doi:10.1089/hum.2012.112. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Human gene therapy

PubMed ID