@article{0b1a5230a075493e807457f766a88585,
title = "A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells",
abstract = "Nine dogs with hemophilia A were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9–11.3% of normal FVIII levels. In two of nine dogs, levels of FVIII activity increased gradually starting about 4 years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of the integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A, while emphasizing the importance of long-term monitoring for potential genotoxicity.",
author = "Nguyen, {Giang N.} and Everett, {John K.} and Samita Kafle and Roche, {Aoife M.} and Raymond, {Hayley E.} and Jacob Leiby and Christian Wood and Assenmacher, {Charles Antoine} and Merricks, {Elizabeth P.} and Long, {C. Tyler} and Kazazian, {Haig H.} and Nichols, {Timothy C.} and Bushman, {Frederic D.} and Sabatino, {Denise E.}",
note = "Funding Information: We are grateful to members of the Sabatino and Bushman laboratories for help and suggestions. We acknowledge the Research Vector Core at the Children{\textquoteright}s Hospital of Philadelphia for production of the SC AAV vectors and the Penn Vector Core at the University of Pennsylvania for preparing the TC AAV vectors. We thank M. Keiser for assistance with immunohistochemistry and A. Messer for assisting with the analysis of the canine samples. We also thank N. Hoepp for discussions on canine liver clinical pathology. We thank S. Sherrill-Mix for help with statistical analysis. This work was supported by grants from the National Institutes of Health (RO1HL083017 (H.H.K.), R24HL63098 and N0175N92019D00041 (T.C.N.), RO1HL126850 (D.E.S.) and RO1AI082020, RO1CA241762, RO1HL142791 and U19AI149680 (F.D.B)). We also acknowledge support from the Penn Center for AIDS Research (P30AI045008) and the PennCHOP Microbiome Program (F.D.B.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jan,
doi = "10.1038/s41587-020-0741-7",
language = "English (US)",
volume = "39",
pages = "47--55",
journal = "Biotechnology",
issn = "1087-0156",
publisher = "Nature Publishing Group",
number = "1",
}