Nature Medicine: Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6–8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial (NCT01639690). Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC—primary endpoint) and engraftment of genetically modified autologous CD34+ cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy—secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34+ cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors.

β-Thalassemias are hereditary anemias caused by over 400 mutations that affect the β-globin gene (HBB), resulting in absent or insufficient production of the β chain of hemoglobin (Hb) (https://www.ithanet.eu/db/ithagenes). Treatment of the severe form of the disease, known as transfusion-dependent β-thalassemia (TDT), requires lifelong transfusions to supply Hb-replete red blood cells (RBCs), which the thalassemic bone marrow is unable to produce. This treatment is life-saving but fraught with medical complications. The only curative therapy is the transplantation of allogeneic hematopoietic stem cells (HSCs) harboring functional globin genes, but this option is not available to the vast majority of patients with thalassemia, for whom a suitably matched related donor cannot be found. Although bone marrow transplantation from a matched related donor carries a low risk of morbidity and mortality, few patients opt for alternative transplant modalities owing to the potentially serious risks associated with matched-unrelated or mismatched transplants.

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