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 UCL.
The findings from the trials, which were led by researchers at UCL, Great Ormond Street Hospital for Children (GOSH), Hospital Infantil Universitario Niño Jesús, Madrid (Spain) and University of California, Los Angeles (UCLA), are published in the New England Journal of Medicine and involved nine children aged five months to nine years with severe leukocyte adhesion deficiency I (LAD-I).
LAD-I is a rare primary immunodeficiency, where children do not have a functioning immune system and are constantly struggling to fight infections. As a result, they are frequently hospitalised. Without treatment, they rarely live past two years old.
The disease is caused by genetic variants in the gene responsible for the production of CD18. CD18 is a protein on the surface of white blood cells that allows them to get out of the blood stream and to the site of an infection.
In heathy people, once white blood cells reach a site of infection, they can tackle it without much concern, but for children with severe LAD-I, the faulty white blood cells can't get to where they are needed, leaving the children vulnerable to frequent and escalating infections.
The current standard treatment is a bone marrow transplant to provide stem cells from a donor with the correct genetic code to create white blood cells that have CD18. This requires a matching donor and is not available in time for most patients.
Even if successful, a bone marrow transplant has some serious and potentially life-threatening side effects like rejection of donor cells and graft-versus-host-disease, where the donated cells attack the recipient's body.
The new gene therapy research, sponsored by Rocket Pharmaceuticals Inc., involves clinicians taking the patient's own stem cells and modifying them with a gene therapy that instructs the cells to create the missing protein needed to get out of the blood stream and fight infection. The corrected cells are then returned to the patients where they can start to develop a working immune system.
This investigational gene therapy uses the patient's own cells to avoid the risk of rejection or graft-versus-host disease.
The study shows that all nine children treated in this trial have responded well to treatment and, after one to two years of treatment, are all surviving with fewer symptoms. Their skin and dental lesions, infections and inflammatory symptoms have resolved and the children have been able to resume a relatively normal life.
After treatment, all children in the trial had their blood analysed and were found to have the CD18 protein that they need to fight infections in the long term, allowing them to stop taking their previous medications for severe LAD-I.
One child in the trial, Eisa, who was just 10 months old when he joined the trial, recently started school. Now four years old, he was able to have critical heart surgery after the gene therapy where his recovery was just as expected for any child without severe LAD-I. The researchers say this would've been previously unimaginable.
Researchers are continuing to follow patients to explore the long-term effects of the treatment.
Professor Claire Booth (UCL Great Ormond Street Institute of Child Health and GOSH) said: "We are thrilled for Eisa and all the children in this trial but also because this success has far-reaching implications, beyond severe LAD-I.
"As this process has been shown to be successful for such a complex disease, we could move towards a blueprint to treat many other diseases. Gene therapy is being explored by teams at GOSH and our partners for blinding conditions, muscular dystrophies, cancer and others - the possibilities are really far reaching.
"Families like Eisa's put their faith in us, in the research to offer them a chance. It's a long, often uncertain journey with difficult decisions but the way families approach these trials is something to be celebrated and applauded."
The trial was carried out across three sites: GOSH, UCLA Mattel Children's Hospital, and Hospital Infantil Universitario Niño Jesús in Madrid.
Study co-author, Dr Donald Kohn (UCLA) said: "Seeing our patients in three different countries, offered a chance at childhood without serious infections and without frequent hospital visits, is a testament to how beneficial this therapy could be."
Dr Julian Sevilla (Hospital Infantil Universitario Niño Jesús) said: "This trial demonstrates once again how gene therapy could potentially cure diseases that would otherwise be incurable without adequate stem cell donors, with shorter hospital stays and fewer adverse side effects."
Eisa's story
As a baby, Eisa experienced repeated infections and was only a few weeks old when tests confirmed that he had severe LAD-I. When Eisa was around four months old, his family learned about the trial, and the team at GOSH determined Eisa was eligible to join the trial. Prior to this, the family considered a bone marrow transplant but there was no matched donor in the family.
Eisa stayed at GOSH during the height of the COVID pandemic and lockdown restrictions, so the family had to spend this time in isolation. It was difficult, but they never left his side.
In February 2021, Eisa received the therapy and almost four years on, his life has changed dramatically for the better. With the help of the GOSH physiotherapy team, he has continued to grow stronger and started to play football.
Eisa is described as a bubbly and friendly child and loves being outdoors and spending time with his siblings, something he wasn't well enough to do beforehand. Eisa's dad Safdar said that with the help of this gene therapy, "it is amazing to see Eisa having the chance to live a normal life."
