Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction
Authors
Zhong, LiMalani, Nirav
Li, Mengxin
Brady, Troy
Xie, Jun
Bell, Peter
Li, Shaoyong
Jones, Haven
Wilson, James M.
Flotte, Terence R.
Bushman, Frederic D.
Gao, Guangping
UMass Chan Affiliations
Department of PediatricsDepartment of Microbiology and Physiologcal Systems
Gene Therapy Center
Document Type
Journal ArticlePublication Date
2013-05-15Keywords
DependovirusGenetic Vectors
Gene Therapy
Carcinoma, Hepatocellular
UMCCTS funding
Biomedical Engineering and Bioengineering
Medical Genetics
Medical Immunology
Metadata
Show full item recordAbstract
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.Source
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 siteDOI
10.1089/hum.2012.112Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30238PubMed ID
23621841Related Resources
Link to Article in PubMedRights
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: http://online.liebertpub.com. Publisher PDF posted as allowed by the publisher's author rights policy at http://www.liebertpub.com/nv/resources-tools/self-archiving-policy/51/.ae974a485f413a2113503eed53cd6c53
10.1089/hum.2012.112