| Abstract: |
The genetic treatment of the haemoglobinopathies poses the general challenge of how to modify a gene or its product in a haemopoietic stem cell and how to achieve regulated and sustained transgene expression in vivo in the progeny of a stem cell. The studies briefly summarized earlier attest to the creativity and renewed vigour applied recently to developing novel strategies for the treatment of thalassaemia and sickle cell disease. Nonetheless, there is a large gap between biological experimentation which provides proof of principle, and clinical evaluation. This gap reflects limitations in our understanding of the elementary processes that are utilized for the ultimate purpose of gene therapy. The missing knowledge will come from research in different fields. However, there is a need to bring together highly specialized investigators from different backgrounds who share the common aim of addressing issues in gene transfer, gene expression, and transplantation biology that specifically arise in the development of genetic therapies. Viral-mediated gene transfer is the most advanced form of gene delivery today, owing to the relative efficiency it provides in stably delivering genetic material to primary haemopoietic cells. Recent progress in the retroviral transfer of human globin genes brightens the prospects of this approach, which is therefore likely to be the first one to enter clinical trials in the realm of the haemoglobinopathies. The implementation of these trials nonetheless depends on future breakthroughs in gene transfer efficiency, the control of transgene expression, and stem cell expansion and transplantation - issues that extend far beyond the realm of globin disorders. It seems highly optimistic to expect a meaningful clinical trial for haemoglobinopathies before the year 2000. However, we hope to know by then, from animal studies, whether viral vectors that accommodate up to 8 kb of DNA and incorporate genetic determinants of chromatin structure are able to achieve stable, erythroid-specific, and sufficiently elevated globin transgene expression after integration in the chromosomes of haemopoietic stem cells. |
