A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells.
Authors: Giang N. Nguyen, John K. Everett, Samita Kafle, Aoife M. Roche, Hayley E. Raymond, Jacob Leiby, Christian Wood, Charles-Antoine Assenmacher, Elizabeth P. Merricks, C. Tyler Long, Haig H. Kazazian, Timothy C. Nichols, Frederic D. Bushman and Denise E. Sabatino.
Dogs with hemophilia A due to an intron 22 inversion were treated with AAV vectors driving expression of canine FVIII and followed for over 11 years. Canine FVIII expression persisted in all dogs and increased in at least 2. This is the longest duration of expression reported to date in any animal model. Vector integration studies revealed genomic integration mostly of vector fragments but in at least on case intact vector. Vector integration occurred at or near multiple genes including transcription factors in the canine genome. Clonal expansion was also observed. Despite these findings of vector integration and clonal expansion, no hepatocellular carcinomas were found. Future work is planned to determine whether or not AAV vector integration is causing clonal expansion. The data strongly support the safety of current AAV vectors but also highlight areas for potential improvements and optimization.