An investigational gene therapy has successfully restored immune function in children with an ultra-rare immune disease.

Severe leukocyte adhesion deficiency I (LAD-I) is a genetic condition that affects approximately one in a million people in the world. It is caused by mutations in the ITGB2 gene, which produces a protein called CD18 that helps white blood cells travel from the bloodstream to infection sites. Without this protein, children with LAD-I do not have a properly functioning immune system, leaving them more susceptible to recurrent bacterial and fungal infections. Without treatment, they rarely live past two years old. Now, an international team of researchers has conducted a small-scale study of an investigational gene therapy administered to nine children and published their results in the New England Journal of Medicine. All participating children who were administered the therapy have responded well, and their symptoms of LAD-I have reduced.

Professor Claire Booth, consultant paediatric immunologist at Great Ormond Street Hospital for Children (GOSH), and co-lead author, said: 'We are thrilled for... 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.'

The current method of treatment for LAD-1 is an allogeneic haematopoietic stem-cell transplantation (HSCT) – commonly known as a bone marrow transplant – where stem cells are taken from the bone marrow of a donor and transferred to the patient in order to 'reset' their immune system. In contrast, the new treatment is an autologous HSCT, meaning that the patient's own stem cells are used. This eliminates the potential of the patient rejecting the donor cells or the development of graft-versus-host disease.

Haematopoietic stem cells were extracted from the patients, aged five months to nine years, and fused with a functional copy of the ITGB2 gene using a lentiviral vector. These were then administered back to the patients, leading to the production of healthy immune cells capable of fighting infections.

Lentiviral vectors are derived from HIV and are highly efficient at integrating transgenes into the genome. The lentiviral vector used in the therapy is self-inactivating, which means it is 'switched off' after delivering the stem cells.

The Phase II clinical trial consisted of a small cohort because the condition is so rare. The nine patients were monitored for two years across three clinical trial sites: GOSH in London, the Hospital Infantil Universitario Niño Jesús in Madrid, Spain, and the University of California Los Angeles Mattel Children's Hospital. No severe adverse events were reported, and all patients had sufficient levels of the CD18 protein in their blood, allowing them to stop taking their previous medications.

Six of the patients have enrolled in a long-term follow-up study and will continue to be monitored for a total of 15 years where the therapy's efficacy and safety will be assessed. One of these patients, Eisa Hussain, received the gene therapy in February 2021 at GOSH after no matched donor for a bone marrow transplant could be found.

Eisa's father commented: 'Great Ormond Street told us they couldn't find a bone marrow match so they offered the gene therapy... Since then, because of this treatment, he has actually been able to fight infections himself. Great Ormond Street saved his life. He wouldn't be able to have the life he has now without those services.'

The availability of genetic and genomic testing for people and families affected by rare disease will be discussed at the free-to-attend online event Rare Disease Genomic Testing: How Do We Make Access Equitable and Timely?, taking place online on Wednesday 18 June 2025.

Find out more and register here.