Gene therapy deemed safe, effective for children with Wiskott-Aldrich syndrome

Gene therapy appeared safe and effective for children with Wiskott-Aldrich syndrome without a suitable donor for hematopoietic stem cell transplantation, according to a study published in Nature Medicine.

“This work shows the potential for gene therapy to act as a safe alternative [for patients with Wiskott-Aldrich syndrome (WAS)] when transplant is a less favorable option,” Adrian J. Thrasher, MBBS, PhD, professor in pediatric immunology and Wellcome Trust principal research fellow at the University College London Great Ormond Street Institute of Child Health, said in a press release.

Errors that occur in a section of DNA on the X chromosome cause WAS, reducing the patient’s ability to fight infection. It almost exclusively impacts boys at a rate of approximately three in every million children worldwide.

Symptoms include easy bruising, bloody diarrhea and prolonged bleeding after minor injuries. These patients also are more vulnerable to infection and are at higher risk for certain cancers.

WAS can be life threatening without proper treatment, most often due to bleeds in the brain. Also, most patients who do not get treatment and who lack the WAS protein do not survive beyond their second or third decade of life.

Allogeneic hematopoietic stem cell transplantation (HSCT) with a human leukocyte antigen (HLA)-compatible donor is the first-line treatment for WAS. According to the researchers, however, only approximately 20% of patients can find a donor.

When a suitable donor is not available, the researchers found gene therapy via the infusion of gene-corrected autologous hematopoietic stem cells (HSCs) is an option. The procedure uses a harmless lentivirus to deliver healthy genes into the patient’s system.

The study involved seven children and one young adult patient treated at Necker-Enfants Malades Hospital in Paris and Great Ormond Street Hospital in London, with a median patient age at the time of therapy of 5.25 years (range, 0.8-30 years) and a follow-up of 4 to 9 years (median, 7.6 years) after gene therapy.

All the patients saw reductions in the frequency and severity of infections and were able to discontinue their pre-therapy anti-infection prophylaxis. Also, seven of the patients experienced resolution of their eczema manifestations, and the eighth experienced a significant decrease in SCORing Atopic Dermatitis results, from 52 to 15.

Although all the patients had severe microthrombocytopenia before the therapy, none of them experienced spontaneous, severe bleeding afterward even though they had below-normal platelet counts. Also, none of them required platelet transfusions.

T-cell and B-cell counts increased to reach normal age-matched reference values as well. The researchers associated the growth in T cells with sustained clinical benefits. Whereas IgA levels reached age-matched reference levels in all patients, the researchers continued, IgM levels remained below normal in four patients. Five patients were able to discontinue immunoglobulin replacement therapy.

Although the researchers observed some persistent autoimmune manifestations, the level of circulating autoantibodies normalized after treatment.

Also, there were no graft failures or any other treatment-related adverse effects after gene therapy, with safe and diverse insertion profiles and no concerning clonal expansion.

“This research continues to show the benefits of gene therapy, as we see our patients begin to live lives like their friends and not have to worry about everyday bumps and scrapes,” Thrasher said.

Reference:

• Gene therapy trial aids children with severe immune disorder. https://www.gosh.nhs.uk/news/gene-therapy-trial-aids-children-with-severe-immune-disorder/. Posted April 4, 2022. Accessed April 4, 2022.