Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1
Claire Booth, Julián Sevilla, Elena Almarza, Caroline Y. Kuo, Josune Zubicaray, Dayna Terrazas, Gráinne O’Toole, Maria Chitty-Lopez, Grace Choi, Eileen Nicoletti, Janel Long‐Boyle, Augustine Fernandes, Kritika Chetty, Satiro De Oliveira, Crystal Banuelos, Jinhua Xu‐Bayford, Antonella Lucía Bastone, Philipp John-Neek, Connie Jackson, Theodore B. Moore, Kimberly Gilmour, Axel Schambach, Michael Rothe, Sanchali Kasbekar, Gayatri R. Rao, Kinnari Patel, Gaurav Y. Shah, Adrian J. Thrasher, Juan A. Bueren, Jonathan Schwartz, Donald B. Kohn
Abstract
BACKGROUND: , which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure. METHODS: , and followed them for 24 months. The primary efficacy end point of the phase 2 study was survival without allogeneic HSCT (HSCT-free survival) at least 1 year after marne-cel infusion and at 2 years of age among the patients who were younger than 1 year of age at enrollment, tested against a null hypothesis of survival of 39% of the patients. We also report interim data from six patients enrolled in the long-term follow-up study. RESULTS: Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure. HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001). All the patients who were enrolled at younger than 1 year of age were alive beyond 2 years of age. Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved. The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower. CONCLUSIONS: In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I. (Funded by Rocket Pharmaceuticals and the California Institute for Regenerative Medicine; ClinicalTrials.gov numbers, NCT03812263 and NCT06282432.).