Genetic modification of human hematopoietic stem cells

Transplantation of genetically modified hematopoietic stem cells is a potential therapy for a variety of genetic and acquired blood disorders, such as severe combined immunodeficiencies, thalassemia and AIDS. Genetic modification of stem cells can be carried out ex vivo, by transducing bone marrow or peripheral blood stem cell-rich fractions with viral vectors carrying therapeutic genes. These vectors must be able to transduce long-term repopulating stem cells, and allow appropriate transgene expression. Recent improvements in cell culture and vector technology are providing new tools for obtaining clinically relevant numbers of genetically modified hematopoietic stem cells from a standard bone marrow harvest. The proof of the therapeutic potential of this technology is the successful therapy of two different forms of severe combined immunodeficiencies, rare genetic disorders associated with recurrent infections that may be fatal in the first years of life. These pivotal trials, however, have also uncovered the oncogenic potential of random retroviral insertions into the human genome. For non life-threatening disorders, the risk of insertional oncogenesis may be unacceptable, and new research is needed to develop new, safer and more efficient gene transfer vectors for clinical application.