Slow and Steady Wins The Race? Progress in the Development of Vectors for Gene Therapy of β-Thalassemia and Sickle Cell Disease.

The cloning of the human β-globin genes more than 20 years ago led to predictions that β-thalassemia and sickle cell disease would be among the first monogenic diseases to be successfully treated by gene replacement therapy. However, despite the worldwide enrollment of more than 3,000 patients in approved gene transfer protocols, none have involved therapy for these diseases. This has been due to several technical hurdles that need to be overcome before gene replacement therapy for β-thalassemia and sickle cell disease can become practical. These problems include inefficient transduction of hematopoietic stem cells and an inability to achieve consistent, long-term, high-level expression of transferred β-like globin genes with current gene transfer vectors. In this review we highlight the relationships between understanding the fundamental mechanisms of β-globin gene locus function and basic vector biology and the development of strategies for β-globin gene replacement therapy. Despite slow initial progress in this field, recent advances in a variety of critical areas provide hope that clinical trials may not be far away.