FDA Approves Kresladi: First Gene Therapy for Severe Leukocyte Adhesion Deficiency Type I

What Is Leukocyte Adhesion Deficiency Type I and Why Is It So Dangerous?

Leukocyte Adhesion Deficiency Type I is caused by mutations in the ITGB2 gene, which encodes the CD18 protein — a critical component of beta-2 integrin adhesion molecules on white blood cells. Without functional CD18, neutrophils and other leukocytes cannot adhere to blood vessel walls or migrate to sites of infection. This leaves patients profoundly immunocompromised despite having normal or even elevated white blood cell counts in their blood.

Children with severe LAD-I typically present in the first weeks of life with delayed separation of the umbilical cord, recurrent bacterial and fungal infections, and impaired wound healing. The condition is estimated to affect roughly 1 in 1 million live births. Without a bone marrow transplant — the only prior curative option — the majority of children with the severe form do not survive past age two. However, bone marrow transplantation carries significant risks including graft-versus-host disease, particularly when a fully matched donor is unavailable.

How Does Kresladi Gene Therapy Work?

Kresladi (marnetegragene autotemcel) is an ex vivo gene therapy. The process begins with collecting the patient's own hematopoietic stem cells (CD34+ cells) from bone marrow. These cells are then transduced in a laboratory setting using a lentiviral vector that carries a functional copy of the ITGB2 gene. Once the corrected gene is integrated into the stem cells, the modified cells are infused back into the patient after a conditioning regimen designed to make space in the bone marrow for the new cells to engraft.

Once engrafted, the corrected stem cells begin producing white blood cells that express functional CD18 protein on their surface. This restores the ability of neutrophils and other leukocytes to adhere, migrate, and fight infections normally. Because the therapy modifies the patient's own cells, it eliminates the risk of graft-versus-host disease that accompanies allogeneic bone marrow transplants. Clinical data supporting the approval demonstrated that treated patients achieved sustained CD18 expression on their neutrophils and experienced significant reductions in severe infections.

What Does This Approval Mean for the Future of Gene Therapy in Rare Immune Disorders?

The approval of Kresladi builds on a series of recent gene therapy milestones for primary immunodeficiencies. Previous approvals and clinical programs have targeted conditions such as severe combined immunodeficiency (ADA-SCID) and cerebral adrenoleukodystrophy, demonstrating that ex vivo lentiviral gene correction of hematopoietic stem cells can provide lasting clinical benefit. For LAD-I specifically, this approval is transformative because many patients lack suitable bone marrow donors, leaving them with limited treatment options.

The broader significance lies in the regulatory and scientific precedent. Each successful gene therapy approval for a rare disease helps refine manufacturing processes, regulatory pathways, and long-term follow-up protocols that can be applied to other monogenic disorders. The FDA has increasingly supported accelerated development of gene therapies for ultra-rare conditions through designations such as Rare Pediatric Disease Priority Review Vouchers and Breakthrough Therapy designation. However, challenges remain, including the high cost of one-time gene therapies, the need for specialized treatment centers, and the importance of long-term safety monitoring for insertional mutagenesis risks associated with integrating viral vectors.