The β hemoglobinopathies, beta-thalassemia (β-thalassemia) and sickle cell disease (SCD), are the most common monogenic diseases worldwide and constitute a growing and major burden on health services in many nations.1 These disorders result from mutations in the β-globin gene locus that lead to the production of insufficient (β0 or β+) or abnormal (βS) globin protein. In β-thalassemia, reduced β globin production leads to an imbalance in the ratio of α to β chains leading to ineffective erythropoiesis, chronic hemolysis, and profound anemia. While improvements in red blood cell transfusion and chelation practices have improved their prognosis, patients with transfusion-dependent β-thalassemia continue to suffer organ damage due to iron overload and other complications of their disease. Allogeneic hematopoietic stem cell transplantation, while curative, confers significant risks of morbidity and mortality and is limited by donor availability. Gene transfer achieved by transplantation of the patient's own stem cells that have been genetically-modified with a corrected gene offers a potential alternative curative therapy. The first proof of principle of its therapeutic benefit was reported a decade ago utilizing a β-globin expressing lentivirus in a patient with transfusion-dependent thalassemia (βE/β0).2 2018 brought exciting advances in this field.
Dr. Alexis Thompson and colleagues reported interim results of two early-phase clinical studies (HGB-204 and HGB 205) evaluating the safety and efficacy of gene therapy for β-thalassemia using a lentiglobin vector (LentiGlobin BB305) expressing β-globin engineered with a single amino acid substitution (T8Q).3 This amino acid change strongly inhibits the polymerization of sickle hemoglobin in patients with SCD and also allows precise quantification of vector-derived therapeutic globin expression in vivo. Twenty-two patients with transfusion-dependent β-thalassemia (12-35 years of age) underwent myeloablative busulfan conditioning followed by infusion of autologous CD34+ stem/progenitor cells transduced ex vivo with a lentiviral vector. Follow up after transplantation ranged from 15 to 42 months. No safety issues were attributed to the vector, no replication-competent lentivirus was detected, and no clonal dominance developed in any of the patients. At 12 months after infusion, the median number of unique integration sites was 1,646 per patient (range, 202-5,501 sites) in HGB-204 and 5,322 (range, 756-8,685 sites) in HGB-205. The median vector copy number at 15 months was 0.3 copies per diploid genome (range, 0.1-0.9 copies) in HGB-204 and 2.0 copies per diploid genome (range, 0.3-4.2 copies) in HGB-205.
Among the 13 non–β0/β0 genotype patients, all but one was able to forgo red cell transfusions after gene therapy. Among the nine patients with a β0/β0 genotype or homozygosity for the IVS1-110 mutation, a β+ genotype with trace endogenous βA expression that presents with a severe phenotype, six had a median HbAT87Q of 4.2 g/dL (range, 0.4-8.7 g/dL) and continued to receive transfusions. However, their number of annual transfusions was reduced by 74 percent (range, 7%-100%). The remaining three patients with β0/β0 genotype or two copies of IVS1-110 mutation had not received transfusions for 14 to 20 months. In the two studies, blood HbAT87Q levels correlated with blood vector copy number. The studies were not powered to conclusively assess determinants of response. Updates on the HGB-204 study reported at the 2018 ASH Annual Meeting4 demonstrate a sustained clinical benefit with up to 3.5 years of follow-up.
Transfusion-dependent β-thalassemia is a severe genetic disease. Gene therapy offers a potentially transformative option for these patients. Phase III trials are now underway5 and should help to determine the benefit, risks, and cost/benefit analysis of this approach.
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Competing Interests
Dr. Keel indicated no relevant conflicts of interest.
