β-Thalassemias are hereditary disorders caused by reduced or absent synthesis of the β chain of haemoglobin. Due to this, patients often require regular blood transfusion and lifelong care. Researchers at the Center for Cell Engineering, Memorial Sloan Kettering Cancer Center (New York, USA) have designed a lentiviral globin vector (TNS9.3.55) expressing a normal β-globin gene. The functional gene is transduced into CD34+ hematopoietic stem cells isolated from the patient and infused through autologous stem cell transplantation.
This study, recently published in the Journal Nature Medicine, included four adult patients with β-Thalassemias.1 They were infused with the lentiviral globin vector and monitored for six to eight years. The study’s primary endpoint was the safety and tolerability of the infusion-product after reduced-intensity conditioning (RIC). In addition, the secondary endpoint of the study included engraftment of autologous cells, expression of transduced globin gene and post-transfusion requirements.
The conditioning and cell product infusion were generally safe without unexpected side effects. Two patients had reduced transfusion requirements due to stable but low expression of the β-globin gene. Transfusion independence was not achieved. These data suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but requires minimum transduction with a lentiglobin vector in CD34+ autologous cells. The globin vectors also showed non-erythroid activity due to integrations near cancer-related genes. Therefore, it is essential to monitor patients treated with globin vectors cautiously.
In conclusion, the lentivirus based gene therapy showed encouraging results and an acceptable safety profile in a few β-Thalassemia patients. However, patients need constant and active monitoring to negate or manage any putative side effects of this gene therapy. Future phase II/III trials are required to assess the efficacy and safety of this gene therapy.