[Constitutional hematologic diseases. Perspectives of gene therapy]

Technical advances in molecular genetics have succeeded in elucidating the molecular basis of many hereditary diseases. The characterization of these abnormalities is currently giving rise to the concept of pharmacological treatment or, if possible, organ replacement (bone marrow grafting or liver transplantation). Genotherapy aims at replacing a single deficient gene by a functional gene introduced into an autologous, and therefore unrejectable, tissue. The haematopoietic stem cells are excellent targets for gene transfer, since the procurement, ex vivo, manipulation and reimplantation of these cells are easily performed. Several constitutional blood diseases would benefit from a causative treatment if a group of truly multipotent, self-renewing stem cells could integrate a transgene compensating for the hereditary deficit. The problems inherent in gene transfer, targeting on haematopoietic stem cells, mode of introduction of the transgene and its expression at a sufficiently high level are presented. Important progress has recently been made in this fields, and therapeutic applications to man can now be envisaged, although not all obstacles have been overcome. This concerns, in particular, the globin deficiency gene in beta thalassemia.