Article Impact Level: HIGH Data Quality: STRONG Summary of New England Journal of Medicine, 392(17), 1698–1709. https://doi.org/10.1056/NEJMoa2407376 Dr. Claire Booth et al.
Points
- A phase 1-2 study tested marne-cel gene therapy in nine children with severe LAD-I, using autologous stem cells modified with a lentiviral vector carrying the ITGB2 gene.
- The therapy achieved 100 percent survival without stem cell transplantation at one year, with no gene therapy-related adverse events and significant improvements in clinical symptoms.
- While no graft failures occurred, serious side effects were linked to the busulfan conditioning regimen before infusion.
- Infection-related hospitalizations, prolonged hospital stays, and serious infections were dramatically reduced by over 70 to 80 percent after treatment compared to pre-treatment levels.
- The results suggest marne-cel could be a safe and effective long-term alternative to HSCT for patients with severe LAD-I who lack suitable donors.
Summary
This phase 1-2 multinational, open-label study investigated the efficacy of marnetegragene-autotemcel (marne-cel), a gene therapy for treating severe leukocyte adhesion deficiency type I (LAD-I), a condition caused by defects in the CD18 integrin subunit that leads to life-threatening infections. Nine children with severe LAD-I were treated with marne-cel, which involves autologous CD34+ hematopoietic stem cells transduced with a lentiviral vector containing the human ITGB2 gene. The study aimed to assess the primary endpoint of survival without allogeneic hematopoietic stem cell transplantation (HSCT) 1 year after infusion, and also evaluated long-term outcomes. The patients were followed for 24 months.
Results demonstrated that marne-cel was highly effective, with 100% HSCT-free survival 1 year after infusion (95% CI, 66% to 100%; P<0.001). No graft failures or gene therapy-related adverse events were reported. However, serious adverse events related to the myeloablative busulfan conditioning regimen were observed. All patients under 1 year of age at enrollment survived beyond 2 years. The treatment led to significant clinical improvements, including resolution of pretreatment neutrophilia and skin abnormalities. Infection-related hospitalizations decreased by 74.45%, prolonged infection-related hospitalizations dropped by 81.95%, and serious infections were reduced by 84.90% compared to pre-treatment levels.
In conclusion, the use of lentiviral vector-transduced autologous CD34+ hematopoietic stem cells as a gene therapy for severe LAD-I proved to be highly successful. This approach offers a potential alternative to HSCT with a low incidence of infections and no adverse events linked to the gene therapy itself. This approach could provide a long-term solution for patients with LAD-I, especially those unable to access suitable donors for traditional HSCT.
Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2407376
References Booth, C., Sevilla, J., Almarza, E., Kuo, C. Y., Zubicaray, J., Terrazas, D., O’Toole, G., Chitty-Lopez, M., Choi, G., Nicoletti, E., Long-Boyle, J., Fernandes, A., Chetty, K., De Oliveira, S., Banuelos, C., Xu-Bayford, J., Bastone, A. L., John-Neek, P., Jackson, C., … Kohn, D. B. (2025). Lentiviral gene therapy for severe leukocyte adhesion deficiency type 1. New England Journal of Medicine, 392(17), 1698–1709. https://doi.org/10.1056/NEJMoa2407376
