Retrovirus-mediated gene transfer into human hematopoietic stem cells.

Human hematopoietic stem cells genetically modified by retroviral-mediated gene transfer may offer new treatment options for patients with genetic disease. The potential of gene-modified hematopoietic stem cells as vehicles for gene delivery was first illustrated by the demonstration that hematopoietic systems of lethally irradiated mice can be reconstituted with retroviral vector transduced syngeneic bone marrow, and that these cells can in turn provide genetically marked progeny which persist in blood and marrow over extended time periods. In contrast, hematopoietic stem cells from large animals prove difficult to transduce with retroviral vectors and are consequently less likely to function as vehicles for long-term gene therapy. Indeed, clinically relevant levels of gene transfer into large animal and human hematopoietic stem cells has not been widely achieved. The need for improved retroviral vector systems and for understanding the biology of hematopoietic stem cell gene transfer continue to fuel intense research activity. Preliminary results from human stem cell gene marking and gene therapy trials currently underway are encouraging. This contribution reviews the underlying concepts relevant to retroviral-mediated gene transfer into hematopoietic stem cells. We survey the evolution of approaches for gene transfer into hematopoietic stem cells, from murine and large animal models to the first human clinical trials. Finally, we discuss new strategies which are currently being pursued.