Gene therapy for beta thalassemia: preliminary results from the phase I/II Tiget-Bthal trial of autologous hematopoietic stem cells genetically modified with GLOBE Lentiviral Vector.
In a phase I/II trial, Marktel et al. report patients with transfusion-dependent beta thalassemia had a significantly reduced need for blood transfusions after a single infusion of cells carrying corrected genes. The results suggest gene therapy could offer a viable alternative to stem cell transplantation – currently the only curative therapy for this condition – for patients who do not meet the criteria for a stem cell transplant or cannot find a matched stem cell donor.
Beta thalassemia syndromes are a group of inherited anemias affecting hundreds of thousands of people worldwide; about 56 000 babies with the most severe forms of the disorder are born each year. Beta thalassemia causes malfunctions in red blood cells and can lead to severe anemia and other complications. More than 200 genetic variations have been associated with the disease, with severity of symptoms varying by a patient’s specific genetic mutation. Many with the disorder require frequent blood transfusions for the rest of their lives.
This investigational gene therapy aims to deliver corrected genes directly into the bone marrow to allow a patient’s body to manufacture red blood cells that produce normal hemoglobin. To test the approach, researchers extracted stem cells from seven patients (three adults and four children, all of whom required regular blood transfusions due to disease severity) and then infected the cells with a non-pathogenic virus carrying the correct gene. After conditioning each patient with chemotherapy to make space for new stem cells to proliferate, or graft, into the bone marrow, the stem cells carrying the correct genetic material were infused into the patients’ bone marrow.
This research follows several other clinical trials of beta thalassemia gene therapies, some of which also have had promising results; however, this approach varies from previous gene therapies in that it involves a different design of the viral vector, uses a different conditioning regimen for the patient, and is the first beta thalassemia stem cell gene therapy to be delivered directly into the bone marrow, where blood cells are made.
After a median of 16 months of follow-up, five of the seven patients showed a marked reduction in the number of blood transfusions needed. Three pediatric patients required no blood transfusions beginning one month after receiving the gene therapy.
„Our study suggests that gene therapy can correct the disease, resulting in transfusion independence,“ said lead study author Sarah Marktel, MD, of San Raffaele Hospital and SR-Tiget (San Raffaele Telethon Institute for Gene Therapy) in Milan, Italy. „Although the number of patients is small, our preliminary results also suggest the benefit could be greater in children than in adults. Our hypothesis is that younger stem cells in pediatric patients may be more favorably corrected by gene therapy and in general may lead to better engraftment and performance.“
Compared to previous trials in which the genetically modified stem cells were introduced into the bloodstream via intravenous infusion, the patients in this trial began showing evidence of successful engraftment sooner after receiving the therapy, suggesting that infusing the cells directly into the patients’ bone marrow can make a difference.
The results also reveal an encouraging safety profile, with no gene therapy-related adverse reactions apart from the side effects typically associated with the chemotherapy used for conditioning, such as infection. The researchers are now in the process of administering the gene therapy to three additional pediatric patients.
ASH Annual Meeting 2017, abstract #355