Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case

作者：Pilar Puig-Serra, Pilar Puig-Serra, Ana Hinckley-Boned, Ana Hinckley-Boned, María Tristán‐Manzano, Paula Rı́o, Paula Rio, Raúl Torres, Raúl Torres, Sandra Rodríguez, Sandra Rodríguez, Francisco Martı́n · 发表于：Human Gene Therapy · 年份：2025 · DOI：10.1177/10430342251372474 · 被引用次数：8 · 研究领域：Biomedical Ethics and Regulation

Seven cases of hematological malignancy reported in recipients of Skysona™ (elivaldogene autotemcel) have reignited long-standing concerns about insertional mutagenesis in lentiviral vector (LV)-based gene therapy. Here, we dissect the molecular and clinical evidence underlying these events, place them in the broader context of over 300 patients treated with LV-modified hematopoietic stem and progenitor cells (HSPCs), and review the real-world safety record of LV-engineered chimeric antigen receptor T cells. We show that cancers associated with Skysona are mechanistically linked to the use of a potent viral MNDU3 promoter probably combined with intensive conditioning and growth-factor support, whereas LV products employing weak or physiological promoters continue to display an excellent safety profile. With event rates <0.6/100 patient-years, lower than those after autologous HSCT, the therapeutic index of approved LV-HSPC advanced therapy medicinal products remains favorable. Ongoing optimization of vector design, conditioning, and long-term surveillance, together with emerging genome-editing platforms, is expected to further mitigate residual risk.