Low incidence of hepatocellular carcinoma in mice and cats treated with systemic adeno-associated viral vectors

作者：Rita Ferla, Marialuisa Alliegro, Margherita Dell’Anno, Edoardo Nusco, John M. Cullen, Stephanie Smith, Tyra G. Wolfsberg, Patricia O’Donnell, Ping Wang, Anh‐Dao Nguyen, Randy J. Chandler, Zelin Chen, Shawn M. Burgess, Charles H. Vite, Mark E. Haskins, Charles P. Venditti, Alberto Auricchio · 发表于：Molecular Therapy — Methods & Clinical Development · 年份：2020 · DOI：10.1016/j.omtm.2020.11.015 · 被引用次数：49 · 研究领域：Virus-based gene therapy research、Cancer Research and Treatments、Viral Infectious Diseases and Gene Expression in Insects

gene transfer because of their combined efficacy and safety. However, insertional mutagenesis with the subsequent development of hepatocellular carcinomas (HCCs) has been recurrently noted in newborn mice treated with high doses of AAV, and more recently, the association of wild-type AAV integrations in a subset of human HCCs has been documented. Here, we address, in a comprehensive, prospective study, the long-term risk of tumorigenicity in young adult mice following delivery of single-stranded AAVs targeting liver. HCC incidence in mice treated with therapeutic and reporter AAVs was low, in contrast to what has been previously documented in mice treated as newborns with higher doses of AAV. Specifically, HCCs developed in 6 out 76 of AAV-treated mice, and a pathogenic integration of AAV was found in only one tumor. Also, no evidence of liver tumorigenesis was found in juvenile AAV-treated mucopolysaccharidosis type VI (MPS VI) cats followed as long as 8 years after vector administration. Together, our results support the low risk of tumorigenesis associated with AAV-mediated gene transfer targeting juvenile/young adult livers, although constant monitoring of subjects enrolled in AAV clinical trial is advisable.