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Gene therapy for thalassemia normalizes hemoglobin

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Patients in developing countries could see benefit

Lentiviral vector hematopoietic stem cell (HSC) gene therapy represents a promising alternative to matched-sibling donor HSC transplants for treatment of beta thalassemia, with studies to date showing a safety profile that surpasses transplants from unrelated or alternative donors.

The prospect of a curative treatment raised by the work of Dr. Thompson and her colleagues also shows the feasibility of transfusion independence for beta0/betaE patients, who carry the most common beta thalassemia genotype, and a significant reduction in transfusions even for patients with the more severe beta0/beta0 genotype.

Beta thalassemia has greatest prevalence in North Africa, the Middle East, and Asia, where access to treatments is limited and patients’ prognoses are often grim. Gene therapy for beta thalassemia could thereby represent the first large-scale implementation of this intervention in developing countries.

Bringing HSC gene therapy to more patients will require not just the availability of autologous HSCs, but of high-quality vector and reliable, high-volume manufacturing of transduced cells.

Harnessing this still-evolving technology to bring a potentially curative treatment to patients in developing countries is an exciting, but challenging, frontier for physicians and researchers involved with gene therapy.

Alessandra Biffi, MD, is director of the gene therapy program at Dana Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center, Boston. She serves on the board of directors of the American Society of Gene and Cell Therapy. These remarks were adapted from an accompanying editorial ( N Engl J Med. 2018;378[16]:1551-2 ).



Most beta thalassemia patients were off transfusions at a median of 26 months after receiving gene therapy via a lentiviral vector, according to new results of two phase 1/2 studies regarding the use of LentiGlobin in transfusion-dependent beta thalassemia.

Of 13 patients who did not have the most severe beta0/beta0 genotype, all but 1 has become transfusion independent post transplant. Among patients who either had the beta0/beta0 genotype or had two copies of the IVS1-110 mutation, transfusions were down a median 73% annually, and three of these patients with more severe thalassemia became transfusion independent.

At the time of last data collection, hemoglobin levels in individual patients ranged from 8.2-13.7 g/dL.

“No clonal dominance related to vector integration was observed,” wrote Alexis Thompson, MD, and her collaborators, and replication-competent lentivirus had not been found in any patients.

Hematopoietic cell transplant (HCT) is an option primarily for younger beta thalassemia patients who have an HLA-matched sibling donor, the researchers wrote in the New England Journal of Medicine. Gene therapy represents an alternative to the current standard of care for patients who are not candidates for allogeneic HCT, which – without a good match – carries increased risk for rejection and graft-versus-host disease.

Patients with beta thalassemia aged 35 years or younger and without advanced organ damage were enrolled in the two studies, one conducted internationally and one conducted at a single site in France.

There were some protocol differences between the two studies; notably, the French study used enhanced red cell transfusion for 3 or more months before stem cell mobilization “to enrich for bona fide hematopoietic stem cells in the harvested CD34+ cell compartment by suppressing the erythroid lineage expansion and the skewing that is seen in beta thalassemia,” wrote Dr. Thompson, professor of pediatrics at Northwestern University, Chicago, and her colleagues.

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