A team led by Prof. Marina Cavazzana, working at Necker Hospital for Sick Children, AP–HP, and the Imagine Institute (AP–HP/Inserm/Paris Descartes University) performed gene therapy on a 13–year–old patient with severe sickle cell anaemia in October 2014 as part of a phase I/II clinical trial. Conducted in collaboration with Prof. Philippe Leboulch (CEA/Faculties of Medicine at Paris–Sud and Harvard Universities), who developed the vector used, and supervised the preclinical studies, this innovative treatment provided complete remission from the clinical signs of the disease, and the correction of biological signs. Results (15–month follow up after transplantation) were published in the New England Journal of Medicine on 2 March 2017, and confirm the efficacy of this new therapy of the future.

Sickle cell disease, a serious form of chronic anaemia of genetic origin, is characterised by the production of abnormal haemoglobin and deformed (falciform or sickle–shaped) red blood cells, due to a mutation in the gene encoding beta–globin. This disease is associated with very serious episodes of pain caused by vaso–occlusive crises. It also causes lesions in all the vital organs, great sensitivity to infection, iron overload and endocrine disorders. Haemoglobinopathies affect an estimated 7% of the world’s population. Among them, sickle cell disease is considered the most common, with 50 million people carrying the mutation, i.e. who are at risk of transmitting the disease or actually have it. Abnormalities in the beta–globin gene, i.e. sickle cell disease and beta–thalassaemia, are the most widely distributed inherited diseases in the world, more common than all other genetic diseases combined.

The clinical trial, coordinated by Prof. Marina Cavazzana, was conducted at Necker Hospital for Sick Children, AP–HP, and the Imagine Institute.

The first phase involved taking haematopoietic stem cells, the source of all blood cell lineages, from the patient’s bone marrow. A viral vector carrying a therapeutic gene, previously developed to treat beta–thalassaemia, was then introduced into these cells in order to correct them. This lentiviral vector, capable of carrying long complex segments of DNA, was developed by Prof. Philippe Leboulch, and is produced on a large scale by the American company bluebird bio.

The treated cells were then reinjected intravenously into the young patient in October 2014. During his subsequent period in hospital, the adolescent then received care in the Paediatric Immunohaematology Unit at Necker Hospital for Sick Children, in collaboration with Prof. Stéphane Blanche and Dr Jean–Antoine Ribeil.

Fifteen months after transplantation with the corrected cells, the patient no longer requires blood transfusions, no longer suffers from vaso–occlusive crises, and has fully resumed his physical and academic activities. “We also note that the therapeutic protein from the vector, which strongly inhibits pathological sickling, is remarkably highly expressed and effective,” explains Prof. Philippe Leboulch.

“With this gene therapy approach, we hope to develop future clinical trials and enrol a high number of patients with sickle cell disease, in Île de France and throughout the national territory,” says Prof. Marina Cavazzana.