Investigational gene therapy gives children with rare immune disorder a new lease on life

An investigational gene therapy has successfully restored immune function in all nine children treated with the rare and life-threatening immune disorder called severe leukocyte adhesion deficiency-I, or LAD-I, in an international clinical trial co-led by UCLA.

LAD-I is a genetic condition that affects approximately one in a million people in the world. It is caused by mutations in the gene that produces CD18, a protein that enables white blood cells to travel from the bloodstream to infection sites.

In the absence of this critical protein, individuals with severe LAD-I—most of whom are diagnosed within their first months of life—are left vulnerable to dangerous, recurrent bacterial and fungal infections. Survival beyond childhood is rare without treatment.

In a study published in the New England Journal of Medicine, senior author Dr. Donald Kohn reports two-year outcomes for nine patients aged 5 months to 9 years who received the therapy across three clinical trial sites: UCLA Mattel Children’s Hospital, Great Ormond Street Hospital in London, or GOSH, and the Hospital Infantil Universitario Niño Jesús in Madrid. Dr. Claire Booth, leader of the London trial site, and Dr. Julian Sevilla, leader of the Madrid site, are co-lead authors.

All nine children in the trial—a small cohort because the condition is so rare—responded well to the treatment and are living with no disease symptoms. Their skin lesions and severely inflamed gums, hallmarks of LAD-I, have resolved, and they are able to fight off infections like their peers who were born with healthy immune systems.

“These children are no longer defined by their diagnosis,” said Kohn, a distinguished professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

“Seeing them healthy and thriving without serious infections, without frequent hospital visits, is a testament to how consistently beneficial this therapy is.”

How LAD-I gene therapy restores immune function

The only currently available treatment for LAD-I is a bone marrow transplant from a matched stem cell donor. For those individuals lucky enough to find a matched donor, bone marrow transplants still carry the risk of life-threatening side effects including graft-versus-host disease, a condition in which donated cells attack the recipient’s body.

The investigational therapy, developed by Rocket Pharmaceuticals, Inc., genetically corrects patients’ blood stem cells, allowing them to become their own stem cell donor and potentially eliminating many of the known risks of bone marrow transplants.

First, patients’ blood stem cells are collected and then amended using a lentiviral vector, a modified virus designed to safely deliver genetic material into cells. The vector carries a functional copy of the affected gene coding for CD18 to the patients’ blood stem cells, which are then infused back to the patient to produce healthy immune cells capable of fighting infections.

Kohn and his colleagues report that all patients were found to have sufficient levels of the CD18 protein, normalized white blood cell counts and significantly fewer severe infections requiring hospitalization. Additionally, no severe adverse events related to the gene therapy were reported, and all patients remain free of graft failure or adverse immune reaction.

Of the nine patients, six have enrolled in a long-term follow-up study through UCLA, where they will be monitored for a total of 15 years each to assess the therapy’s sustained efficacy and safety.

The trial’s results underscore the potential of gene therapy to provide “durable, life-changing benefits” for individuals with rare genetic disorders, said Kohn, who is also a distinguished professor of pediatrics and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The gene therapy is currently under review by the U.S. Food and Drug Administration, which is reviewing the Biologics License Application. A successful outcome will support the opportunity to treat more children so they can also achieve healthier lives.

“This therapy presents a new path forward in treating these rare immune conditions and reducing the burdens and risks for patients,” said Booth, a consultant in pediatric immunology and gene therapy at GOSH. “It’s a momentous breakthrough for families facing this devastating disease.”