Severe leukocyte adhesion deficiency-I (LAD-I) is caused by biallelic deleterious variants in ITGB2, resulting in <2% CD18 expression and impaired leukocyte extravasation, particularly neutrophils. Affected infants and children experience recurrent, life-threatening bacterial and fungal infections, poor wound healing, and significant mortality in the absence of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although alloHSCT can be curative, many patients lack suitable donors and remain at risk for graft-versus-host disease (GvHD), graft failure, and transplant-related morbidity and mortality. Treatment with a durable autologous hematopoietic stem cell (HSC) gene therapy was developed to address these limitations.
To evaluate the long-term safety and efficacy of RP-L201 (marnetegragene autotemcel), an autologous CD34+ HSC gene therapy using a Chim-CD18-WPRE lentiviral vector incorporating ITGB2, we investigated restoration of CD18 expression, normalization of neutrophil function, and reduction in infection-related morbidity in children with severe LAD-I.
Children ≥3 months old with severe LAD-I were enrolled in the phase I/II study (NCT03812263). CD34+ cells obtained via G-CSF/plerixafor mobilization and apheresis were transduced ex vivo with RP-L201 and infused following therapeutic drug-monitored myeloablative conditioning. Endpoints included survival without alloHSCT, restoration of peripheral blood (PB) polymorphonuclear (PMN) CD18 expression, peripheral blood mononuclear cell (PBMC) vector copy number (VCN), integration site analysis, resolution of baseline leukocytosis, and incidence of infection-related hospitalizations. All treated patients entered the long-term follow-up (LTFU) study (NCT06282432).
Nine patients (age 9.8-117.4 months at infusion) received RP-L201 and were followed for a median (range) of 50.92 (42.6-67.9) months as of the June 18, 2025, LTFU data cut. AlloHSCT-free survival was 100% with no cases of graft failure. PBMC VCN/cell rose to 0.42-2.4 at month 3 and remained stable through month 12 (mean 1.73) with persistent long-term VCN levels across months 42-60. All patients achieved sustained PB PMN CD18 expression within or approaching the target levels, maintained through >3.5 years post-infusion. Longer-term results demonstrate markedly lower annualized incidences of prespecified serious infections, infection-related hospitalizations, and prolonged infection-related hospitalizations after RP-L201 treatment relative to pre-treatment incidences. No new skin or oral infections occurred in the LTFU period. RP-L201 was well-tolerated; no RP-L201-related adverse events occurred. Integration site analyses demonstrated polyclonal integration patterns without dominant or expanding clones.
RP-L201 conferred durable engraftment, sustained CD18 restoration, and significant reductions in infection-related morbidity in nine children with severe LAD-I, with at least 3.5 years of follow-up. All nine patients are alive without alloHSCT. There were no RP-L201-related adverse events. These updated results support autologous HSC gene therapy as an effective alternative to alloHSCT with a favorable risk-benefit profile for severe LAD-I.
