Selective expansion of transduced cells for hematopoietic stem cell gene therapy

Although gene transfer into hematopoietic stem cells holds a considerable therapeutic potential, clinical trials targeting this cell compartment have achieved limited success. Poor transduction efficiency with gene transfer vectors used in human studies has hindered delivering therapeutic genes to clinically relevant numbers of target cells. One way to overcome the low-efficiency problem is by selecting or expanding the number of genetically modified cells to a suprathreshold level to achieve clinical efficacy. This approach may be further classified into 2 categories: one is to transfer a drug resistance gene and eliminate unmodified cells with cytotoxic drugs, and the other is to confer a direct growth advantage on target cells. This review aims at an overview of recent advances involving these strategies, with some details of "selective amplifier genes," a novel system that we have developed for specific expansion of genetically modified hematopoietic cells.