RETROVIRUS-MEDIATED GENE-TRANSFER INTO HUMAN HEMATOPOIETIC STEM-CELLS

Human hematopoietic stem cells genetically modified by retroviral-medi ated gene transfer may offer new treatment options for patients with g enetic disease, The potential of gene-modified hematopoietic stem cell s as vehicles for gene delivery was first illustrated by the demonstra tion that hematopoietic systems of lethally irradiated mice can be rec onstituted with retroviral vector transduced syngeneic bone marrow. an d that these cells can in turn provide genetically marked progeny whic h persist in blood and marrow over extended time periods [1-4]. In con trast, hematopoietic stent 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 hematopo ietic stern cells has trot been widely achieved. The need for improved retroviral vector systems and for understanding the biology of hemato poietic stem cell gene transfer continue to fuel intense research acti vity. Preliminary results from human stem cell gene marking and gene t herapy trials currently underway are encouraging. This contribution re views the underlying concepts relevant to retroviral-mediated gene tra nsfer into hematopoietic stem cells. We survey the evolution of approa ches for gene transfer into hematopoietic stein cells, from murine and large animal models to the first human clinical trials. Finally, we d iscuss new strategies which are currently being pursued.