期刊
NATURE MEDICINE
卷 28, 期 4, 页码 789-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01751-0
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资金
- BioMarin Pharmaceutical
Factor VIII gene transfer using valoctocogene roxaparvovec (AAV5-hFVIII-SQ) through a single intravenous infusion has shown clinical benefits lasting 5 years in patients with severe hemophilia A. This study investigated the molecular mechanisms underlying the sustained expression of AAV5-hFVIII-SQ-derived FVIII in the liver. The results demonstrated persistent episomal vector structures and provided insights into potential mechanisms mediating interindividual variability in transgene expression.
Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial (NCT02576795), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.
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