Gene therapy reduces need for transfusions in severe blood disorder

People with severe beta-thalassemia currently depend on others to donate blood for the repeated transfusions they need. Monkeybusinessimages/iStock/Thinkstock

Beta-thalassemia is one of the most common genetic diseases in the world. It’s a blood disorder that reduces production of hemoglobin. Hemoglobin is the iron-containing protein complex in red blood cells that carries oxygen to cells throughout the body. Hemoglobin is made of two proteins, called the alpha- and beta-globin subunits. Genetic mutations in the genes for either subunit can cause a blood disorder.

Nearly 400 mutations in the beta-globin gene have been found to cause beta-thalassemia. Some mutations prevent the production of any beta-globin. Others allow some beta-globin to be produced but in reduced amounts. People with the most severe forms of beta-thalassemia need monthly transfusions of healthy red blood cells starting in childhood and for the rest of their lives.

A previous study tested gene therapy for one patient with transfusion-dependent beta-thalassemia. Researchers collected hematopoietic stem cells (immature cells that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets) from the patient. They added the normal beta-globin gene to the cells and transplanted them back into the patient. The patient has been transfusion-free for more than six years.

To further test the safety and effectiveness of the approach, an international collaboration of two research teams carried out companion phase 2 clinical trials with 22 patients who had severe beta-thalassemia. They followed the patients’ outcomes for 15 to 42 months. The work was supported in part by NIH’s National Center for Advancing Translational Sciences (NCATS). Results were published in the New England Journal of Medicine on April 19, 2018.

Nine of the patients had the most severe form of beta-thalassemia, with two copies of genes that eliminate beta-globin production. After gene therapy, this group experienced a 74% reduction in annual blood transfusions. Three of these patients were able to stop receiving transfusions entirely. Thirteen of the patients had a slightly less severe form of the disease. None of these patients needed blood transfusions following the treatment. Patients only reported the typical cell transplant-related side effects, suggesting that the treatment is safe.

“When you have an anecdote of a single patient, you never know if it will be confirmed. Here, with a multi-center trial in a larger number of patients, we see a convergence of results, and we can measure the magnitude of the therapeutic effect,” says one of the collaboration's co-leads, Dr. Philippe Leboulch at Brigham and Women’s Hospital, Harvard Medical School, and the University of Paris. “There is room for improvement, as we'd like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease.”

The team has made protocol modifications for a phase 3 trial, which is now recruiting patients. Thirteen of the 22 patients from the current trials have also enrolled in a 13-year follow-up study to continue monitoring the safety and effectiveness of the treatment.

—by Tianna Hicklin, Ph.D.