Gene therapy offers potential to extend lives of children with rare immune disorder

The rare primary immunodeficiency, severe leukocyte adhesion deficiency I (LAD-I), means these children do not have a functioning immune system and are constantly struggling to fight infections. As a result, they are frequently hospitalized. Without treatment, they rarely live past two years old.

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 life-threatening potential side effects like rejection of donor cells and graft-versus-host-disease, where the donated cells attack the recipient’s body.

The gene therapy research 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.

Researchers from Great Ormond Street Hospital (GOSH), University College London (UCL), Hospital Infantil Universitario Niño Jesús, Madrid (Spain) and University of California, Los Angeles (UCLA) have demonstrated successful clinical trial results from this investigational therapy published today in the New England Journal of Medicine.

The study reports outcomes between 18 to 45 months for all nine patients aged five months to nine years who received the therapy across three clinical trial sites: GOSH, UCLA Mattel Children’s Hospital, and Hospital Infantil Universitario Niño Jesús in Madrid.

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 life like their peers.

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 4 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. This was unimaginable before.

As a baby, Eisa experienced repeated infections and was only a few weeks old when tests confirmed that he had severe LAD-I. While at GOSH and when Eisa was around 4 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, and 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”

Researchers are continuing to follow patients to explore the long-term effects of the treatment.

Professor Claire Booth, Mahboubian Professor in Gene Therapy and Paediatric Immunology (UCL) and Consultant Paediatric Immunologist at 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 condition, 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.