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17 Gene Transfer and Stem-cell Transplantation

Malcolm K. Brenner


Hematopoietic stem-cell transplantation and gene transfer may be linked in two ways. Since stem-cell transplantation is used to replace and/or repair hematopoietic or lymphopoietic deficiencies in the host, the most obvious linkage is to use a stem-cell transplant to deliver a therapeutic gene. This approach, in which gene transfer represents the primary therapy while the stem-cell transplant simply represents the means of delivery, has been described in detail (Nienhuis, this volume). Alternatively, however, stem-cell transplantation itself may be the primary therapy, and the process of gene transfer used to enhance its safety and efficacy. It is to this second usage that this chapter is devoted.

Worldwide, more than 30,000 stem-cell transplants are performed each year, the great majority of which are intended to treat patients with malignant disease (Applebaum 1997). One of the fundamental concepts driving modern oncology is that increased doses of cytotoxic drugs will cure increased numbers of patients. Full implementation of this approach is limited by toxicity to normal tissues, among the most sensitive of which are normal hematopoietic stem cells (HSC). The resulting marrow aplasia may cause death from infection or hemorrhage. However, patients can safely be treated with otherwise lethal doses of chemotherapy/radiation if they are then “rescued” from the consequences by infusion of autologous or allogeneic HSCs derived from marrow or from peripheral or placental blood. The success of this approach has led to a steady increase in the number of patients so treated.

To understand how gene transfer can help improve stem-cell transplantation...

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