First gene therapy for β-thalassemia approved

Bluebird Bio’s gene therapy eliminates the need for blood transfusions in patients with β-thalassemia.

The β-hemoglobinopathies, which include β-thalassemia and sickle cell disease, are caused by mutations in the β-globin gene. These gene mutations, of which there are >200 known in the population, result in either abnormal hemoglobin structure or reduced or absent β-globin chains. The clinical manifestations appear several months after birth when gene expression switches from the fetal γ-globin chain to the adult γ-chain that forms hemoglobin A (HbA). The β-thalassemias vary in severity, but patients with the most severe form, β-thalassemia major, rely on monthly red blood cell transfusions to survive. Repeated transfusions, however, eventually result in multi-organ damage due to iron overload, which needs daily chelation therapy. Allogeneic hematopoietic stem cell transplantation is a curative option for β-thalassemia major, when a suitable donor is available. An approach like gene therapy that obviates the need for a matched donor represents a milestone for the field.

Zynteglo is an ex vivo gene therapy that requires the harvesting of a patient’s bone marrow stem cells by apheresis (at least 12 × 10⁶ CD34⁺ cells per kilogram body weight). CD34⁺ cells are then transduced ex vivo with the gene encoding β^A-T87Q-globin via a BB305 lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein G. After patients undergo myeloablative preconditioning with busulfan, the transduced CD34⁺ cells containing the β^A-T87Q-globin gene are given in a single injection (minimum dose 5.0 × 10⁶ cells per kilogram), after which they engraft in the bone marrow and differentiate into red blood cells that produce a therapeutic hemoglobin called HbA^T87Q.

In people with the inherited disorder β-thalassemia, the oxygen-transport protein hemoglobin in red blood cells is defective

The therapy adds a corrective gene whose product combines with α-globin to produce functional hemoglobin, thereby reversing the ineffective red blood cell production seen in β-thalassemia. This potentially curative treatment sped through the regulatory agency to approval, but the steep price tag—€1.6 million ($1.8 million) for a treatment course—could prove burdensome for payers and national healthcare providers seeking options for this relatively common recessive disorder. For patients, however, a one-off, potentially curative treatment could be life changing.

The European Commission based its conditional approval on clinical data from 32 adults and adolescents with transfusion-dependent β-thalassemia treated with Zynteglo, Bluebird Bio has been granted the go-ahead to market its gene therapy for the blood disorder β-thalassemia. Zynteglo gained conditional market approval from the European Commission in June to treat transfusion-dependent β-thalassemia in patients 12 years and older who have no other treatment options. “Becoming transfusion-independent and stopping iron chelation is really a life-changing treatment for patients,” says trial physician Marina Cavazzana, a hematologist at the Necker Children’s Hospital and INSERM, Paris, France. “For example, after the therapy, patients were able to take part in physical activity that would have been impossible before therapy.”

Original published by Nature Biotechnology with slightly modification