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

Molecular Therapy: Methods & Clinical Development

Margherita Dell’Anno¹  Tyra G. Wolfsberg²  Marialuisa Alliegro²  John M. Cullen²  Zelin Chen³  Shawn M. Burgess³  Charles P. Venditti⁴  Randy J. Chandler⁴  Charles H. Vite⁴  Anh-Dao Nguyen⁴  Alberto Auricchio⁴  Mark E. Haskins⁴  Ping Wang⁵  Rita Ferla⁶  Stephanie N. Smith⁶  Edoardo Nusco⁶  Patricia O’Donnell⁶ 

[1] Corresponding author: Rita Ferla, PhD, Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli 80078, Italy.;Medical Genetics, Department of Translational Medicine, “Federico II” University, 80131 Naples, Italy;Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA;North Carolina College of Veterinary Medicine, Raleigh, NC 27607, USA;Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Naples, Italy;

关键词: AAV8;    gene therapy;    lysosomal storage diseases;    MPS VI;    liver;    mouse;   

DOI  :  

来源: DOAJ

【 摘 要 】

Adeno-associated viral (AAV) vectors have emerged as the preferred platform for in vivo 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.

【 授权许可】

Unknown