Kevyn L Hart, Ralph Valentine Crisostomo, Annika Mittelhauser, Lingyu Zhan, Nika Kononov, Kathryn Bradford, Donald B Kohn
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引用次数: 0
Abstract
Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3+ T cells, and in peripheral blood cells from patients treated with autologous CD34+ cells transduced with either a γ-retroviral or lentiviral ADA gene vector to assess transgene mutational profiles. In both CD3+ T cells and ADA-SCID patients' cells treated with the lentiviral vector, we observed significantly higher occurrences of guanine (G)-to-adenosine (A) base substitutions than with the γ-retroviral vector. We hypothesized that this G-to-A mutational signature was due to the APOBEC3 cytosine deaminase protein family. By knocking out APOBEC3 genes in HEK239T packaging cells, APOBEC3-mediated mutagenesis decreased by 91.2% along the transgene in CD34+ transduced cells in comparison to CD34+ cells transduced with lentiviral supernatant packaged in parental HEK293T cells.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.