Marnetegragene autotemcel (marne-cel), an investigational gene therapy, may restore immune function in children with severe leukocyte adhesion deficiency type I (LAD-I), according to findings published April 30 in the
New England Journal of Medicine. The results support the potential of gene therapy as an alternative to allogeneic hematopoietic stem cell transplantation (HSCT), currently the only curative treatment option for patients with this condition.
LAD-I is a rare and life-threatening immune disorder caused by mutations in the ITGB2 gene, which encodes the CD18 protein. Individuals with severe LAD-I, characterized by CD18 neutrophil expression less than 2% of the normal level, are at high risk for recurrent bacterial and fungal infections. Without undergoing HSCT, patients with severe LAD-I are at a higher risk of mortality; only 25 to 39% of affected children survive past the age of 2.
In this phase 1–2 multinational trial, researchers from UCLA, Great Ormond Street Hospital (GOSH), University College London and Hospital Infantil Universitario Niño Jesús treated nine children with marne-cel (Rocket Pharmaceuticals). The gene therapy consists of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing the ITGB2 gene. Patients were followed for 24 months, and the primary endpoint was HSCT-free survival at least one year after marne-cel infusion.
At the end of the study period, all patients survived without undergoing HSCT and remained free of disease symptoms, including skin lesions and severely inflamed gums. Additionally, all three patients who were enrolled younger than 1 year of age were alive after 2 years of age.
The gene therapy also led to sustained immune reconstitution, with CD18 expression on neutrophils exceeding 10% relative to the normal expression in all patients, and durable vector integration in peripheral-blood mononuclear cells and subpopulations, including CD15+ granulocytes. Infection-related hospitalizations decreased by 74%.
According to investigators, the findings suggest that gene therapy may provide durable, life-changing benefits for patients with rare genetic disorders.
“This therapy presents a new path forward in treating these rare immune conditions and reducing the burdens and risks for patients,”
said Claire Booth, MBSS, PhD, a consultant in pediatric immunology and gene therapy at GOSH. “It’s a momentous breakthrough for families facing this devastating disease.”
Six patients have enrolled in a 15-year follow-up study at UCLA to assess the durability and safety of the therapy. While the therapy has not yet been approved for clinical use by any regulatory authority, a biologics license application is currently under review by the Food and Drug Administration.
