Severe Leukocyte Adhesion Deficiency-I (LAD-I) Lentiviral-Mediated Ex-Vivo Gene Therapy: Ongoing Phase 1/2 Study Results

Abstract

BackgroundSevere leukocyte adhesion deficiency-I (LAD-I) is an autosomal recessive inborn error of immunity due to mutations in the ITGB2 gene that encodes the common CD18 subunit of β2-integrins, essential for neutrophil adhesion to the inflamed endothelium and transmigration into tissues. Severe LAD-I, defined as <2% of normal CD18 polymorphonucleocyte [PMN] expression, is characterized by frequent and often refractory bacterial and fungal infections, impaired wound healing, and significant pediatric mortality in the absence of allogeneic hematopoietic stem cell transplant (HSCT). HSCT is potentially curative but limited by donor availability, graft-versus-host disease, and graft failure. The gene therapy RP-L201-0318 (NCT03812263) employs autologous CD34+ cells transduced with a lentiviral vector carrying ITGB2 to restore CD18 expression. MethodsPatients ≥3 months old with severe LAD-I were enrolled. Hematopoietic stem cells (HSCs) were collected via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor and transduced ex-vivo with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning preceded RP-L201 infusion. Patients were followed for safety and efficacy measures, including survival to age two and ≥1-year post-infusion, peripheral blood [PB] PMN CD18 expression, PB vector copy number [VCN], neutrophilia improvement, decrease in infections/hospitalizations, and resolution of skin/periodontal abnormalities. ResultsNine patients (age five months to nine years) received RP-L201; follow-up was 3 to 24 months. RP-L201 cell doses ranged from 2.8 × 106 to 10 × 106 CD34+ cells/kg with a drug product VCN of 1.8 to 3.8. All nine patients demonstrated PMN CD18 restoration (median expression of 56.3%) with sustained, stable genetic markings (median PB mononuclear cell VCN of 1.53). At one year, the overall survival (OS) rate was 100% per Kaplan-Meier estimate. Pre-treatment leukocytosis improved uniformly. Hospitalizations and severe infections were significantly reduced following therapy. No RP-L201-related serious adverse events (SAEs) were reported. Insertion site analyses indicate highly polyclonal integration patterns across the entire cohort. ConclusionRP-L201 has a favorable safety profile and confers durable correction of the severe LAD-I phenotype with improved clinical course in all nine pediatric patients treated as demonstrated via all laboratory and clinical parameters.