Major Challenges for Gene Therapy of Thalassemia and Sickle Cell Disease

摘要

Abstract: Gene therapy utilizing retroviral vectors is being postulated as a real therapeutic alternative for many he-nmopoietic inherited diseases, such as u0002-thalassemia or sickle cell disease. A major limitation of current vectors is their in-nability to achieve efficient gene transfer into quiescent cells, such as human CD34+n cells that reside in the Go phase of the ncell cycle and are highly enriched in hemopoietic stem cells. For that reason, lentiviral vectors (LVs) were proven to be nmore efficient than oncoretroviral vectors. Additional problems of these vectors are a) the low titers observed due to regu-nlatory elements of the u0002-globin locus, used for the improvement of the transgene’s expression, b) the eventual silencing of nthe transgene and c) the toxicity posed on CD34+n cells due to the usage of VSV-G as an envelope protein. These facts nhamper their application for gene therapy of hematopoietic cells. Thus, the major current drawbacks of the field affecting ntherapeutic efficacy, include 1) insufficient transduction efficiency of the target hemopoietic stem cells, 2) inconsistent nexpression of the transgene, 3) putative aberrant expression near integration sites raising safety issues and 4) lack of long nterm expression of the transgene exhibiting eventual silencing. This review presents the current status of globin gene ther-napy for the hemoglobin disorders, reviews the recent results and discusses how the knowledge gained from these trials can nbe used to develop a safe and effective gene therapy approach for the treatment of u0002-thalassemia and SCD.