Development of gene therapy for blood disorders by gene transfer into haematopoietic stem cells.

Haematopoietic stem cells (HSCs) are important target cells for gene therapy of blood disorders due to their pluripotency and ability to reconstitute haematopoiesis following myeloablation and transplantation. HSCs can 'self-renew' and generate new stem cells. Genetically modified stem cells are therefore expected to last a lifetime in the recipient following blood and marrow transplantation, and can potentially cure haematological disorders. Oncoretroviral vectors have been the main vectors used for HSCs because of their ability to integrate into the chromosomes of their target cells. Because oncoretroviral vectors require dividing target cells for successful localization of the preintegration complex and subsequent chromosomal integration of the provirus, only the dividing fraction of the target cells can be transduced. As only a small fraction of haematopoietic stem cells is dividing at any one time, oncoretroviral vector transduction of human HSCs has been low in clinical trials. However, patients with severe combined immune deficiency-X1 (SCID-X1) have recently been treated successfully by gene therapy of autologous bone marrow cells using oncoretroviral vectors containing the common gamma chain gene. While several additional disorders may potentially be treated successfully using oncoretroviral gene transfer to HSCs, many disorders may require much higher gene transfer efficiency than was achieved in the SCID-X1 study. Therefore, lentiviral vectors have recently emerged as promising vectors for human HSCs because they can transduce dividing and nondividing HSCs efficiently, and may become the vectors of choice in the future for treatment of blood disorders where a large fraction of HSCs has to be corrected.