Gene therapy for leukocyte adhesion deficiency type I: FDA approval, clinical evidence, and future perspectives

To the Editor, Leukocyte adhesion deficiency type I (LAD-I) is a rare, autosomal recessive combined immunodeficiency with high early mortality rates due to a mutation in the ITGB2 gene, which prevents white blood cells (WBCs) from effectively fighting infections. A 1988 multicenter retrospective evaluation reported a mortality rate of 75% by the age of 2 years, and those patients with moderate disease in their childhood experienced multiple infections, with mortality reported at 50% by the age of 40. The hallmark features of the disease include recurrent bacterial infections, impaired wound healing, and periodontal disease1. The treatment options are limited to antibiotics for actively occurring infections. In some rare cases, neutrophil transfusions are useful for patients with life-threatening infections, while a major therapy for LAD-I patients is hematopoietic stem cell transplantation, which has a reported survival rate of only 75% in treated patients2. The lack of available donors remains a frequent problem in this therapy, and the significant rate of graft-versus-host disease remains a major issue when using haploidentical donors for hematopoietic stem cell transplantation3. Keeping these challenges in mind, the Food and Drug Administration (FDA) approved Kresladi (marnetegragene autotemcel), the first gene therapy for LAD-I, on 26 March 20264. Kresladi is designed for the treatment of pediatric patients with LAD-I who do not have a suitable matched sibling donor for stem cell transplantation. Biallelic variants in the gene ITGB2 from both parents cause LAD-I in their child. Patients who do not have an human leukocyte antigen-matched sibling donor are usually at risk of morbidity and mortality associated with allogeneic hematopoietic stem cell transplant. Kresladi works by taking the patient’s own hematopoietic stem cells, genetically modifying them, and adding functional variants of the ITGB2 gene. Before reinfusion of a patient’s stem cells, they are typically conditioned to receive chemotherapy. A single dose of stem cells is infused intravenously for the treatment of LAD-I, while also restoring CD18 and CD11a cell surface expression in WBCs4. CD18 and CD11a are major leukocyte adhesion molecules required for neutrophil migration and accumulation at inflammatory sites5. The significance of the intervention was evaluated in an open-label, single-arm, multicenter trial. The evaluation showed an increase in neutrophil CD18 and CD11a cell surface expression at month 12, with a durable therapeutic effect through month 24 post-infusion, encoded by ITGB24. All nine LAD-I patients had 18–42 months of available follow-up6. Higher CD18 and CD11a expression indicated better neutrophil adhesion and function. The approval of the therapy was reported using a surrogate endpoint that is indicative of clinical benefit in LAD-I for approval. The real clinical benefit must still be confirmed through post-marketing requirements4. Data demonstrated large decreases, in comparison with pre-treatment history, in the incidence of infections, combined with evidence of recovery from LAD-I–related cutaneous lesions and restoration of wound repair capabilities, indicating a paradigm shift from management to molecular cure6. The reported side effects during the evaluation in the clinical study included some blood-related concerns like anemia, low platelet counts, and low WBC counts. Some infections were also reported, such as skin infections, upper respiratory infections, and viral infections. Other symptoms included fever, mouth sores, nausea, vomiting, and rash. Some serious adverse effects included increased liver enzymes, indicating possible liver stress, and febrile neutropenia4. Limited availability in low-resource settings remains concerning. The FDA approval of this therapy represents a landmark in rare disease therapeutics but warrants cautious optimism. The approval must be accompanied by a balance between innovation and accessibility. While trials show therapeutic results, the call for long-term safety monitoring remains relevant. As gene therapy continues to progress globally, the advancement of gene therapy infrastructure should be promoted in a way that not only enhances its clinical utility for the treatment of patients but also aids in developing and advancing the techniques and procedures. This innovation may pave the way for a new era of precision medicine, provided its benefits are equitably distributed.