Recombinant Adeno-Associated Virus Integration Sites in Murine Liver After Ornithine Transcarbamylase Gene Correction

This is the authors' abstract. We don't add key points for this paper.

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. Zhong and colleagues use deep sequencing to examine the distribution of integrated AAV genomes in nodules/tumors from the livers of ornithine transcarbamylace (Otc) deficient mice. Using this approach, they report four examples of integration sites in the Dlk1-Dio3 locus; this site has previously been implicated in human hepatocellular carcinoma and may warrant careful monitoring in human clinical trials using AAV vectors.

Supports monitoring for rAAV insertional mutagenesis in human trials; leaves open translation from murine liver tumors.