Autologous Ex Vivo Lentiviral Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I Provides Sustained Efficacy with a Favorable Safety Profile
Year: 2026
Type: article
Abstract: Background Severe leukocyte adhesion deficiency-I (LAD-I) results from biallelic deleterious ITGB2 variants leading to deficient/defective CD18 leukocyte expression and impaired endothelial adhesion and extravasation. Children with <2% of normal CD18 neutrophil expression experience recurrent, life-threatening bacterial and fungal infections, and extensive mortality. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is potentially curative but limited by donor availability, graft-versus-host disease (GvHD), and graft failure (GF). Aims To evaluate the long-term safety and efficacy of RP-L201 (marnetegragene autotemcel), an autologous CD34+ hematopoietic stem cell gene therapy utilizing the Chim-CD18-WPRE lentiviral vector carrying ITGB2, including restoration of peripheral blood (PB) polymorphonuclear cell (PMN) CD18 and CD11 expression. Methods Patients ≥3 months old with severe LAD-I enrolled in the pivotal phase I/II study (NCT03812263), underwent G-CSF/plerixafor mobilization, apheresis, ex vivo transduction of CD34+ cells with RP-L201, and myeloablative busulfan (cAUC 71.6mg/L*h) conditioning, including therapeutic drug monitoring prior to infusion. Assessments included alloHSCT-free survival, PB PMN CD18 expression, PB vector copy number (VCN) and integration site analysis (ISA), leukocytosis normalization, and infection-related hospitalization annualized events. All patients subsequently entered the long-term follow-up (LTFU) study (NCT06282432). Results As of June 18, 2025, nine patients (age at infusion 9.8–117.4 months) were treated and followed for a median (range) of 50.92 (42.6–67.9) months. AlloHSCT-free survival is 100% with no GF. VCN was 0.42–2.4 at 3 months post-infusion and remained durable thereafter with a mean VCN of 1.73 at M12, sustained through M24 and beyond with concomitant sustained PMN CD18 expression. There were no new skin or oral lesions from the end of the parent study to the data-cut date in the LTFU study. Significant infections (either requiring IV antimicrobials or hospitalization) were markedly (90.7%) reduced from pre-infusion through the following 91 days post-engraftment up to the end of the study. RP-L201 was well-tolerated with no discontinuations or RP-L201-related adverse events. ISA demonstrated highly polyclonal integration patterns without evidence of predominant clones. Summary/Conclusion Treatment with RP-L201 results in durable phenotypic correction across all relevant clinical and laboratory parameters of severe LAD-I patients. The long-term benefit-risk profile for RP-L201 remains favorable, with no RP-L201-related adverse events and 100% alloHSCT-free survival.
Source: Journal of Human Immunity
Authors: Claire Booth, Julian Sevilla, Elena Almarza, Caroline Y. Kuo, Josune Zubicaray, Maria Chitty-Lopez, Susan Manganaro, Haojun Ouyang, Bitha Narayanan, Janel Long-Boyle, Augustine Fernandes, Kritika Chetty, Satiro DeOliveira, Crystal Banuelos, Jinhua Xu-Bayford, Phillip John-Neek, Connie Jackson, Theodore B. Moore, Kimberly Gilmour, Axel Schambach, Michael Rothe, Adrian J. Thrasher, Juan A. Bueren, Jonathan D. Schwartz, Donald B. Kohn
Institutions: Great Ormond Street Hospital, University College London, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Hospital Infantil Universitario Niño Jesús, Hospital Universitario Fundación Jiménez Díaz, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, University of California, Los Angeles, University of California, San Francisco, Medizinische Hochschule Hannover, Boston Children's Hospital, Harvard University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7159949430