From Pages to Practice

Published March 1, 2017


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In the age of precision medicine, clinicians and scientists have encouraged the use of technologies to identify the underlying cause of a disease and develop a therapeutic option. This is particularly important when a disease is caused by a genetic aberration and standard therapies are expensive or associated with adverse events. Gene therapy is an example of a potential treatment option that has been used with caution. Use of viral vectors to correct a genetic mutation within cells has been attempted with variable results. Gene therapy research published as case reports and phase I and II trials for a variety of conditions have demonstrated proof of concept.

In the case of sickle cell disease, the causative genetic abnormality was discovered in 1956, yet management options are limited to hydroxyurea and supportive treatments. Allogeneic hematopoietic stem-cell transplantation is the only curative option available for patients with severe sickle cell disease. However, a large proportion of patients do not have access to a suitable donor for an allogeneic stem cell transplant. Ex-vivo gene transfer and autologous hematopoietic stem-cell transplantation may proffer an alternative option for patients with severe sickle cell disease.

In this week’s issue of NEJM, Ribeil and colleagues describe their first patient with severe sickle cell disease who was treated with an anti-sickling b-globin gene introduced into autologous hematopoietic stem cells by a lentiviral vector. The patient in this case report is a 13-year-old boy with HbSS genotype and a history of vasocclusive crises, including two episodes of acute chest syndrome and treatment for bilateral hip osteonecrosis. In addition, he underwent a cholecystectomy and splenectomy for his condition. He had received frequent blood transfusions and hydroxyurea between the ages of 2 and 9 with no significant improvement in symptoms.

Neutrophil engraftment was achieved 38 days after stem-cell transplantation, followed by platelet engraftment at 91 days. HbAT87Q levels rose to 5.5 g per deciliter at 9 months after the stem-cell transplantation and and continued to rise over time. Six months after the stem-cell transplant, total hemoglobin levels were stable between 10.6 and 12.0 g per deciliter and red-cell transfusions were discontinued.

More than 15 months after the gene therapy intervention, no sickle cell disease-related clinical events or hospitalizations had occurred. All regular medication, including those started for pain control, were discontinued. Ferritin levels, which were elevated due to numerous blood transfusions before the intervention, had decreased. Comparison of the proportion of sickled red cells before and after gene therapy could not be meaningfully compared because of the patient’s history of exchange transfusions. However, the investigators noted that the proportion of sickled red cells in the patient’s blood at 6 and 12 months after the intervention was lower than that in untreated patients with sickle cell disease.

Gene therapy studies continue to be in the experimental phase for many conditions ranging from b-thalassemia to Wiskott-Aldrich syndrome. Although this case report had a positive outcome, it is important to ensure sufficient follow up to review the durability of the efficacy and safety of gene therapy in severe sickle cell disease. The results of this study are preliminary and offer hope to patients but it is important to approach the next stage of research into this therapy with caution.

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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.