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15 The Hematopoietic System as a Target for Gene Therapy

Brian P. Sorrentino, Arthur W. Nienhuis


The ability to transfer a gene into repopulating stem cells and to achieve lineage-specific expression in differentiating hematopoietic cells would create many therapeutic opportunities. The hemoglobin disorders, severe β-thalassemia and sickle cell anemia, because of their frequency worldwide and their severe morbidity and mortality, were early targets for human gene therapy. Molecular cloning of the globin genes in the late 1970s (Efstratiadis et al. 1980; Lawn et al. 1980) fueled interest in these diseases as targets for genetic intervention. Demonstration that DNA fragments could be incorporated into the genome of eukaryotic cells by calcium-phosphate-mediated DNA uptake (Pellicer et al. 1978) provided the methodology for attempted gene transfer into stem cells. Reported success in a murine model (Cline et al. 1980) prompted an attempt to treat patients with severe β-thalassemia by introduction of a globin gene into hematopoietic cells using calcium-phosphate-mediated transfection. In retrospect, this attempt carried little, if any, risk to the patients, but it was widely discredited because the very low efficiency of transduction and gene integration achieved by this methodology rendered success very unlikely. Furthermore, the investigators failed to obtain prior approval from the appropriate regulatory bodies before undertaking clinical trials (Anderson and Fletcher 1980).

The field of human gene therapy has evolved substantially from this uncertain beginning. Studies in the murine model provided a sound experimental basis for subsequent work in larger animal models and ultimately for the initiation of human clinical trials. Many additional diseases that are potentially amenable to gene-therapy intervention have been characterized. The...

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