A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells.

Autor: Nguyen GN; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Everett JK; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kafle S; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Roche AM; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Raymond HE; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Leiby J; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wood C; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Assenmacher CA; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Merricks EP; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC Blood Research Center, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Long CT; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC Blood Research Center, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Kazazian HH; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA., Nichols TC; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC Blood Research Center, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Bushman FD; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Sabatino DE; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. dsabatin@pennmedicine.upenn.edu.; Division of Hematology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dsabatin@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2021 Jan; Vol. 39 (1), pp. 47-55. Date of Electronic Publication: 2020 Nov 16.
DOI: 10.1038/s41587-020-0741-7
Abstrakt: 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.
Databáze: MEDLINE
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