Autologous Ex Vivo Lentiviral Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I Provides Sustained Efficacy with a Favorable Safety Profile

BackgroundSevere 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).AimsTo 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.MethodsPatients ≥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).ResultsAs 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/ConclusionTreatment 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.