More than 275,000 infants are born with sickle cell disease worldwide every year. It is caused by a single amino acid substitution in “adult” βA –globin (Glu6Val). Sickle haemoglobin (HbS) renders red cells unable to change shape when passing through small blood vessels. Patients have intensely painful vaso-occlusive crises, leading to irreversible organ damage. Although allogeneic hematopoietic stem-cell transplantation offers curative option, fewer than 18% of patients have access to a matched sibling donor.
A recent paper from Ribeil et al., report’s a patient who received therapeutic ex vivo gene transfer into autologous hematopoietic stem cells and who had complete clinical remission with correction of haemolysis and other disease symptoms.
A boy with the βS /βS genotype was followed at the Necker Children’s Hospital in Paris. He had a history of vaso-occlusive crises, acute chest syndrome, and hip osteonecrosis. He had undergone cholecystectomy and splenectomy. He was treated with hydroxyurea without success and prophylactic red-cell transfusions.
In October 2014, aged 13 years he received an infusion of the gene therapy product. Bone marrow–enriched CD34+ cells were transduced with LentiGlobin BB305 containing self-inactivating lentiviral vector encoding the human HBB variant βA-T87Q. The patient underwent myeloablation with intravenous busulfan. Neutrophil engraftment was achieved on day 38 after transplantation, and platelet engraftment was achieved on day 91 after transplantation.
The patient had expected side effects from busulfan conditioning including neutropaenia, grade anaemia, thrombocytopaenia and infection, all of which resolved with standard measures. No adverse events related to the LentiGlobin BB305–transduced stem cells were reported. Test results for the presence of replication-competent lentivirus were uniformly negative.
The patient was discharged on day 50. More than 15 months after transplantation, no sickle cell disease–related clinical events or hospitalization had occurred which contrasts favourably with the period before the patient began to receive regular transfusions. All medications were discontinued, including pain medication. The patient reported full participation in normal academic and physical activities.
This case report of a patient with sickle cell disease who received gene therapy with the use of lentiviral gene addition of an anti-sickling β-globin variant provides proof of concept for this approach and may help to guide the design of future clinical trials of gene therapy for sickle cell disease.
Ribeil, J. A., S. Hacein-Bey-Abina, E. Payen, et al. (2017). “Gene Therapy in a Patient with Sickle Cell Disease.” N Engl J Med. 376(9): 848-855.