Adding a functional gene to defective blood stem cells is a successful therapy for patients with severe beta thalassemia, according to an international phase-3 clinical trial led by Ospedale Pediatrico Bambino Gesù in Rome, whose results have been published in the New England Journal of Medicine.
Beta thalassemia is an inherited disorder that impairs the production of hemoglobin, the blood protein responsible for transporting oxygen. It affects one per 100,000 newborns per year on average in the world, with a higher incidence in Mediterranean countries, China, India and southeast Asia. Patients need regular blood transfusions to replace the missing hemoglobin, and lifelong pharmacological treatments to reduce the iron excess caused by transfusions. A stem cell transplant from a compatible donor is the only permanent cure, but it holds immunological risks and not all patients can benefit from it.
In a treatment called Beti-cel, short for Betibeglogene autotemcel, stem cells are collected from the patient’s blood and functional genes are added to their DNA via a viral vector. The patient’s body is cleared from abnormal stem cells by chemotherapy and the added stem cells are infused back. “The functional genes sustain long-term production of working hemoglobin”, says Mattia Algeri, hematologist at Ospedale Pediatrico Bambino Gesù, one of the authors of the study. “Our trial participants have been followed up for years now, and their hemoglobin production is stable”.
The treatment has had a complicated history. In May 2019, the European Medicines Agency had granted a conditional market authorization to Beti-cel, for patients aged 12 years or older. In February 2021, the authorisation was temporarily suspended after two participants to a clinical trial on a similar treatment for sickle cell anemia developed acute myeloid leukemia and myelodysplastic syndrome. “Gene delivery by viral vectors holds a non-zero risk for oncogenesis”, says Marco Zecca, director of the Pediatric Hematology/Oncology Unit at San Matteo Hospital in Pavia, not involved in the study, “because the insertion could alter DNA sites regulating cell proliferation”. An investigation and EMA review found that the two blood cancer cases were probably due to inflammation induced by the disease itself. The EMA restored Beti-cel authorization in July 2021.
The latest study1 combines some of the data that earned the conditional authorization with new results on patients under 12. Overall, 20 out of 22 treated patients were able to cease blood transfusions, and in particular 6 out of 7 participants aged less than 12 years. “Now the treatment could be authorized also for children”, says Algeri.
However, the company that markets the treatment has recently announced that it is withdrawing from the European market, after negotiations with several European governments failed to produce an agreement on the pricing of its gene therapies. Algeri expects that Beti-cel will be available in the USA as soon as it gains authorisation from the Food and Drug Administration.
Meanwhile, another gene therapy against beta thalassemia is also under clinical trial at Ospedale Bambino Gesù2. “It restores the production of a different form of hemoglobin present in fetal blood that is not affected by beta thalassemia, normally switched off shortly after birth,” Algeri explains. “Gene editing reverses the switch and restored fetal hemoglobin deputises for the adult one.”Algeri says it could take from 2 to 3 years to win market authorisation.