AAV2-related insertional mutagenesis in human hepatocellular carcinomas: implications for gene therapy

Posted by & filed under Part 02: PERSPECTIVES.

Adeno-associated viral (AAV) vectors have been increasingly used for gene therapy in preclinical and clinical studies. In liver-directed approaches the AAV vectors have emereged as the most promising gene transfer vector in terms of safety and efficacy. A few studies have found increased incidence of hepatocellular carcinomas (HCCs) in mice injected with AAV vectors as newborns whereas no evidence of insertional mutagenesis and cancer were observed in adult mice, in dogs, and in nonhuman primates. In mice which developed cancer the AAV integrated in the Mir341 within the Rian locus that has no orthologues in the human genome.

A recent study published in Nature Genetics found clonal integration of AAV2 in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes (CCNA2, TERT, CCNE1, TNFSF10, and KMT2B) leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. The authors concluded that AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

This paper add important information of the controversial issue of AAV and insertional carcinogenesis and will affect development and design of gene therapy trials with AAV vectors.


Posted by Nicola Brunetti-Pierri, MD

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