Major Challenges for Gene Therapy of Thalassemia and Sickle Cell Disease

Gene therapy utilizing retroviral vectors is being postulated as a real therapeutic alternative for many hemopoietic inherited diseases, such as beta-thalassemia or sickle cell disease. A major limitation of current vectors is their inability to achieve efficient gene transfer into quiescent cells, such as human CD34(+) cells that reside in the Go phase of the cell cycle and are highly enriched in hemopoietic stem cells. For that reason, lentiviral vectors (LVs) were proven to be more efficient than oncoretroviral vectors. Additional problems of these vectors are a) the low titers observed due to regulatory elements of the beta-globin locus, used for the improvement of the transgene's expression, b) the eventual silencing of the transgene and c) the toxicity posed on CD34(+) cells due to the usage of VSV-G as an envelope protein. These facts hamper their application for gene therapy of hematopoietic cells. Thus, the major current drawbacks of the field affecting therapeutic efficacy, include 1) insufficient transduction efficiency of the target hemopoietic stem cells, 2) inconsistent expression of the transgene, 3) putative aberrant expression near integration sites raising safety issues and 4) lack of long term expression of the transgene exhibiting eventual silencing. This review presents the current status of globin gene therapy for the hemoglobin disorders, reviews the recent results and discusses how the knowledge gained from these trials can be used to develop a safe and effective gene therapy approach for the treatment of beta-thalassemia and SCD.