The Ongoing Challenge of Hematopoietic Stem Cell-Based Gene Therapy for β-Thalassemia

Figure 1

Schematic representation of HSC-based gene therapy for β-thalassemia. BM CD34⁺ cells are removed from the patient (right panel), transduced in vitro with the therapeutic globin LV, carrying the preferred envelope glycoproteins, and returned to the patient intravenously. At this stage, and primarily in the case of human HSCs, ex vivo expansion and proliferation can be induced; alternatively, selection of genetically modified HSCs may take place. Both strategies can lead to increased yield of corrected HSCs, which will contribute to the HSC compartment, when returned to the patient. Alternative strategies for obtaining higher yield of CD34⁺ cells are continuously emerging (left panel). These include mobilization of BM CD34⁺ HSCs with mainly G-CSF and then isolation of these cells from peripheral blood. Moreover, iPS cell strategy suggests that somatic cells from the patient can be reprogrammed to iPS cells and after genetic manipulation, involving genetic correction for the mutations by homologous recombination, these cells can give rise to globin-producing HSCs, following directed hematopoietic differentiation.