Lentivirus vectors in β-thalassemia.

Patients with β-thalassemia major require lifelong transfusions and iron chelation, regardless of the type of causative mutations (e.g., β⁰, β(E)/β⁰). The only available curative therapy is allogeneic hematopoietic transplantation, although most patients do not have an HLA-matched, geno-identical donor, and those who do still risk graft-versus-host disease. Hence, gene therapy by ex vivo transfer of a functional β-globin gene is an attractive novel therapeutic modality. In β-thalassemia, transfer of a therapeutic globin gene does not confer a selective advantage to transduced stem cells, and complex DNA regulatory sequences have to be present within the transfer vector for proper expression. This is why lentiviral vectors have proven especially suited for this application, and the first Phase I/II human clinical trial was initiated. Here, we report on the first gene therapy patient with severe β(E)/β⁰-thalassemia, who has become transfusion-independent, and provide methods and protocols used in the context of this clinical trial.