Kresladi Gene Therapy for Severe LAD-I: How FDA Approval Changes Outlook for Rare Immune Disorder 2025 | iMedic

How Does the ITGB2 Gene Defect Cause Severe LAD-I and Why Is Gene Correction a Logical Approach?

Leukocyte Adhesion Deficiency Type I is a monogenic disorder, meaning it arises from defects in a single gene — ITGB2 on chromosome 21. This gene provides instructions for making CD18, a protein that pairs with CD11 subunits to form beta-2 integrin complexes on the surface of white blood cells. These integrins are critical for the multi-step adhesion cascade: neutrophils must first roll along vessel walls, then firmly adhere, and finally transmigrate through the endothelium to reach infected or injured tissue. When CD18 is absent or severely reduced (below 2% of normal levels), neutrophils circulate in the blood but cannot exit the vasculature effectively.

Clinically, this manifests in the neonatal period with delayed separation of the umbilical cord — often beyond three weeks — followed by recurrent soft tissue infections, periodontitis, and impaired wound healing. Characteristically, affected sites show minimal pus formation despite elevated circulating neutrophil counts, because the cells simply cannot reach the tissue. The molecular simplicity of LAD-I — a single gene defect in cells that can be collected, modified, and returned — makes it well-suited for ex vivo gene therapy. By transducing the patient's CD34+ hematopoietic stem and progenitor cells with a lentiviral vector encoding functional ITGB2, Kresladi enables these corrected cells to engraft in the bone marrow and continuously produce neutrophils capable of normal adhesion and migration.

What Clinical Evidence Supported the Approval and What Outcomes Were Observed?

Given the ultra-rare nature of LAD-I, the clinical program for Kresladi enrolled a small number of patients with severe disease who lacked a matched sibling donor for conventional transplantation. The primary efficacy endpoint centered on the proportion of neutrophils expressing CD18 above a threshold associated with clinical benefit, measured at defined intervals following infusion. Published data from the development program indicated that treated children achieved CD18 expression levels sufficient to restore meaningful neutrophil function, with expression persisting over follow-up periods extending beyond two years in some patients.

Secondary endpoints included the frequency and severity of infections requiring hospitalization, the need for prophylactic antibiotics, and overall survival. Investigators reported that treated patients experienced a marked decline in infection-related hospitalizations compared to their own pre-treatment history — an important benchmark in rare disease trials where historical controls or natural history data serve as comparators. Safety assessments focused on engraftment kinetics, the effects of busulfan conditioning, and integration site analysis to monitor for clonal expansion. No cases of vector-related malignancy were identified during the monitored period, though the FDA has mandated 15 years of post-treatment surveillance consistent with agency guidance for all integrating gene therapy vectors. These results, while drawn from a limited cohort, were considered clinically meaningful given the otherwise grim prognosis of untreated severe LAD-I.

What Are the Practical Considerations for Families Considering Kresladi?

One of the most significant practical advantages of Kresladi over allogeneic transplantation is the elimination of the donor search process. For families who receive a LAD-I diagnosis — often in the first weeks of life when infection risk is already escalating — the months-long search for an unrelated matched donor through registries represents critical lost time. With autologous gene therapy, the child serves as both donor and recipient. The apheresis procedure to collect CD34+ stem cells can typically be scheduled promptly after diagnosis confirmation and clinical stabilization.

However, the treatment timeline still involves considerable complexity. After cell collection, the manufacturing process at Rocket Pharmaceuticals' facility requires quality testing before release, during which the child remains on supportive care. The busulfan conditioning regimen, while reduced in intensity compared to protocols used for allogeneic transplant, still carries risks of mucositis, cytopenias, and veno-occlusive disease that require inpatient management. Families should anticipate several weeks of hospitalization around the conditioning and infusion period. Geographic access is also a consideration, as administration will initially be limited to designated treatment centers with the infrastructure and expertise to manage gene therapy patients. Financial navigation will be essential given the expected high cost of the one-time therapy, though outcomes-based payment models and manufacturer-sponsored patient assistance programs may help address affordability barriers.