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Hematopoietic stem cell gene therapy for inherited bone marrow disorders: Past accomplishments and continued challenges

From the time that the genes encoding the defective proteins were cloned for a number of inherited diseases, it became a goal to correct those conditions by restoring the normal gene and thereby, its product. For the inherited disorders affecting the blood and its progenitor cells, the hematopoietic stem cells were the ideal target cells for gene transfer, because the normal gene would then be transferred to all of the progeny cells, theoretically for the lifetime of the recipient. However, the tasks of isolating the hematopoietic stem cells, introducing the new genes in such a manner as to preserve engraftment of the manipulated cells, and achieving long‐term gene expression, have not been straightforward in the clinical trial setting, although there has been moderate success for cells in vitro, and in murine studies. With the report of clinical efficacy of gene transfer in children with X‐linked severe combined immunodeficiency disease, the dream of clinical gene transfer to hematopoietic cells has become a reality. But there are still significant impediments remaining for a number of diseases. The innovations of introduction of synthetic receptors that confer growth advantage, the use of lentiviral vectors with increased stem cell transduction efficiency, and the addition of modified promoter/enhancer sequences to augment and preserve gene expression may bring wider success to gene therapy clinical trials for bone marrow disorders in the near future. J. Cell. Biochem. Suppl. 38: 55–64, 2002. © 2002 Wiley‐Liss, Inc.