An article in Science [Hacein-Bey-Abina et al. (2003) Science 302, 415-419] reports on an investigation into the cause of T-cell leukaemia in two out of ten patients who received retrovirus-mediated gene therapy for X-linked severe combined immunodeficiency (SCID-X1); the therapy successfully corrected the SCID in nine of the ten cases. Nearly three years on, the two youngest patients (aged one and three months at the time of treatment) have developed a form of leukaemia triggered by integration of the gene therapy retrovirus vector near to the promoter region of the LMO2 proto-oncogene. It has previously been considered that the risk of insertional oncogenesis (cancerous changes caused by insertion of a retrovirus near to a gene that regulates cell growth) in gene therapy is small, so the report of it occurring in two out of ten patients is a serious one. The fact that insertion of the retrovirus has occurred in exactly the same position of the chromosome in both cases is also alarming, as it contradicts the common view that insertional events would be not only rare but also random in nature.
A commentary accompanying the report [Williams DA and Baum C (2003) Science 302, 400-401] notes that whilst all gene therapy techniques involving integration of new DNA to the patient’s chromosomes carry a risk of insertional oncogenesis, the disease SCID is fatal if untreated, and that gene therapy offers the highest rates of correction with lower rates of side-effects than bone marrow transplantation, which is the only alternative therapy (and which requires an appropriate donor). It is therefore important to keep in mind the context of fatal disease in which these adverse treatment reactions have occurred. The very young age of the patients, the presence of immune deficiency when treatment was initiated and the precise nature of gene therapy for the particular disease probably all contributed to the development of leukaemia.
Comment: Although this report underlines the importance of a cautious approach to gene therapy trials, it need not represent a barrier to realising the potential clinical benefits of the technology. It will be necessary to minimise the risks of adverse effects such as oncogenesis by developing safer gene vectors, and by considering the particular risks posed by each individual disease and selecting vectors accordingly, but this is not the end of the road for gene therapy.