Thalassemia gene therapy looks good at one year

In 2000, May and colleagues reported that a lentivirus containing a human β-globin gene and sequences from the locus control region (LCR) could be efficiently transferred into hematopoietic stem cells of mice with β-thalassemia minor. In recipient red cells, the human β-globin mRNA and protein were present at levels of 13% of endogenous β-globin per vector copy, and the red cell indices were significantly improved. This was an important advance for the field, demonstrating that lentivirus vectors could overcome the instability of globin retroviral vectors and that high levels of globin gene expression could be achieved. Recent work at the Massachusetts Institute of Technology, St Jude, and the University of Washington has confirmed the soundness of the lentivirus approach.

These results were only the beginning. Many researchers have found that transgene expression from viral vectors can be si-lenced over time. It was also not clear whether the secondary consequences of thalassemia could be corrected by the amount of human β-globin produced. In this issue May and colleagues (page 1902) have laid these concerns to rest. Irradiated thal/+ recipients received transplants of thal/+ marrow transduced with either control or globin lentivirus vectors. The recipients were observed for 40 weeks after transplantation, nearly half the life span of a mouse. Human β-globin mRNA and protein levels were consistently 16% of endogenous β-globin throughout the study period, indicating that no silencing had occurred. In addition, a careful study of extramedullary hematopoiesis in the spleen and iron accumulation in the liver demonstrated that transfer of the humanβ-globin gene restored normal hematopoiesis in the spleen and prevented the accumulation of iron in the liver. These are important findings that demonstrate the feasibility of gene therapy for treating hemoglobinopathies.

Clinical gene therapy of thalassemia has more challenges for May and colleagues. Can gene therapy cure the more severe forms of thalassemia? Are HIV-based lentivirus vectors safe for clinical gene therapy? Preliminary results are promising, but more studies such as this one will be needed to fully answer these questions.