Published on 03.02.2022
In 2014, a 13-year-old boy being followed at Necker Enfants Malades AP-HP Hospital for a severe form of sickle cell disease received the first ever gene therapy. A few years later, in March 2017, the team of Professor Marina Cavazzana, a pediatrician, director of the Department of Biotherapy at Necker-Enfants Malades Hospital and director of the Clinical Investigation Center in Biotherapy, affiliated to the Imagine Institute (Inserm, AP-HP, University of Paris) and a world expert in this innovative therapy, published the first very encouraging clinical results of this approach in the New England Journal of Medicine . After more than a year of treatment, the young patient no longer suffered from painful attacks and no longer needed blood transfusions to alleviate his symptoms. This allowed his life to return to normal.
Today, after seven years of follow-up, the efficacy of the treatment persists with no significant deleterious side effects," says Prof. Marina Cavazzana, "And this success is not an isolated case. In fact, in two new studies published in the British journal Nature Medicine, Prof. Marina Cavazzana and her teams present the promising results of long-term follow-up of cohorts of patients treated by gene therapy.
Gene therapy for sickle cell disease and beta-thalassemia
In the first clinical trial , promoted by bluebird bio, patients suffer from sickle cell disease and β-thalassemia, genetic diseases affecting hemoglobin, the main component of red blood cells. Both diseases are induced by a mutation in the gene coding for ß-globin, the constituent protein of hemoglobin. In the case of sickle cell disease - the most common genetic disease, with 350,000 new cases diagnosed each year worldwide - the mutated hemoglobin becomes rigid and the red blood cells take on the shape of sickles that obstruct the blood vessels. This leads to extremely painful seizures, severe anemia and increased risk of infection, with progressive loss of organ function. In the case of β-thalassemia, the mutated gene causes a deficiency in the production of β-globin, resulting in severe anemia.
For both diseases, the only curative treatment at present is the transplantation of hematopoietic stem cells (the source of blood cells), taken from the donor's bone marrow. However, the curative impact of this approach is limited by the lack of availability of compatible donors: they are found in only about 25% of cases. There are therefore treatments available to reduce the pain of sickle cell patients, including blood transfusion, which consists of punctually replacing the stock of diseased red blood cells with healthy red blood cells, iron chelators to reduce its overload, and painkillers. The problem is that these regular treatments are cumbersome and target the consequences, not the causes, of the disease, which progresses with severe organ damage.
An alternative is gene therapy. This aims to modify a gene or insert a new gene into the DNA of patients' stem cells. This genetic manipulation consists of using a transporter, in this case a lentiviral vector developed by Pr Philippe Leboulch*, capable of carrying a new genetic sequence to the nucleus of the cell. This new sequence is then integrated into the genome, before being translated and transcribed into healthy hemoglobin. "We evaluated the long-term benefits of this approach on 7 patients at the Necker Children's Hospital. Among them, 4 had beta-thalassemia and 3 had sickle cell disease, including the 2014 patient," says Marina Cavazzana.
The result: 6 of the 7 patients have completely cured their chronic anemia and all associated symptoms: pain of vaso-occlusive crises in the case of sickle cell disease, with a correction of iron metabolism. "Patients treated with gene therapy no longer need blood transfusions and have stopped all pain medications, so there is a clinical and biological cure. This proves that gene therapy can be an alternative solution in cases where these patients lack an HLA-matched donor," says Professor Cavazzana.
Gene therapy for Wiskott-Aldrich syndrome
In the second study, the teams of Prof. Cavazzana in Paris and Prof. Thrasher in London achieved the same success in Wiskott-Aldrich syndrome, a primary immune deficiency affecting white blood cells . This disease is due to a mutation in the WAS gene that causes a defect in the WASp protein, which is essential for cell migration, proliferation and activation. As a result, the immune system of patients is present but the function of T, B and NK (Natural Killer) lymphocytes as well as dendritic cells is severely impaired, leading to infections and, in the most severe cases, autoimmunity. In addition, this disease presents a significant hemorrhagic risk with spontaneous bleeding that can lead to the death of patients, due to severe thrombocytopenia.
In the clinical trial conducted in parallel at Necker-Enfants Malades Hospital and Great Ormond Street Hospital (London), the 8 patients included all had a very severe form of the disease and were not eligible for bone marrow transplantation, hence their inclusion in this gene therapy clinical trial. Result: the long-term effects (median of 7.6 years) are very encouraging.
By integrating a new genetic sequence encoding a healthy WASp protein into patients' hematopoietic cells (precursors of blood cells, including immune cells), doctors were able to correct the main symptoms of the disease, including eczema and severe infections; and improve bleeding and autoimmunity. "All treated patients had a significant reduction in bleeding episodes," says Marina Cavazzana. However, in 5 patients, the number of blood platelets remained below normal values. For the rest, our work proves that the reconstitution of T and B lymphocyte immunity is very good. And we did not find any long-term adverse effects of the gene therapy.
This clinical result is all the more promising since one of the patients included in the cohort was an adult in his thirties who was also able to reconstitute his cellular immunity, with a production of naive T cells and a functional thymus. "This proves that even in adults with a long history of the disease, we can obtain a correction through this strategy," says the scientist. Further studies are already underway to further optimize the long-term effects of this innovative therapy.
 J.A. Ribeil et al., N Engl J Med, 376, 848-855, 2017.
 E. Magrin et al., Nature Medicine, 2022.