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A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells
- Source :
- Nature Biotechnology. 39:47-55
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- Fviii activity
0303 health sciences
Liver cytology
Genetic enhancement
Cell
Biomedical Engineering
Bioengineering
Biology
Applied Microbiology and Biotechnology
Virology
03 medical and health sciences
genomic DNA
0302 clinical medicine
medicine.anatomical_structure
Long term learning
hemic and lymphatic diseases
medicine
Molecular Medicine
Liver function
Gene
030217 neurology & neurosurgery
030304 developmental biology
Biotechnology
Subjects
Details
- ISSN :
- 15461696 and 10870156
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Nature Biotechnology
- Accession number :
- edsair.doi...........c3ee22b1fdc663cae7d19813bc5d7b3f