Replacement genes used to treat an inherited immune disorder could trigger cancer, new research carried out on rodents suggests. The study, published in the journal Nature, shows that treating mice with a normal copy of the gene defective in X-linked severe combined immune deficiency (X-SCID) results in cancer of the white blood cells in a third of the animals. The scientists say that the study highlights the need for longer-term follow-up in studies designed to test the safety of new gene therapy treatments. However, UK gene therapy researcher Adrian Thrasher says that the results could have been caused by artificially high levels of the gene in the animals.
The team, based at the Salk Institute for Biological Studies in La Jolla, California, say their findings could help explain one of the three cases of leukaemia in a French X-SCID gene therapy trial. Two of the cases are thought to have arisen after the therapeutic gene activated a gene known to be involved in cancer, but the new study suggests that the therapeutic gene itself may also pose a risk. The researchers followed mice treated with the IL2RG gene - which is missing or faulty in people affected by X-SCID - and followed them up for 18 months, three times longer than any previous study. They found that a third of the animals developed cancer of the white blood cells, at an average age of ten months. 'These results suggest that curing X-SCID by replacing IL2RG in the manner it is currently being done puts patients at an increased risk of developing cancer', said team member Niels-Bjarne Woods.
Ten patients affected by X-SCID have so far been treated in the French trial, based at the Necker Hospital in Paris. While most have responded extremely well to the therapy, the trial was halted for a second time in January 2005, after a third patient developed symptoms of leukaemia. Two of the affected boys are now in remission, but the other died, and the trial is currently continuing on a case-by-case basis. Children affected by SCID have a faulty gene that means they have no working immune system, so their bodies cannot fight infections. This life-threatening condition is sometimes called 'bubble boy' disease as, unless they can be successfully treated with a matched bone marrow transplant, patients must spend their lives in a sterile environment.
Woods says that the new study could help explain the occurrence of leukaemia in one of the French patients, in whom the therapeutic gene did not activate a cancer-causing gene. In the affected mice, the IL2RG gene inserted itself at different places in the animals' DNA, ruling out the possibility that any cancer genes had been activated. The fact that the leukaemia did not appear until 2-3 years after the gene therapy treatment suggests that 'preclinical experimental treatments involving transgenes should include long-term follow-up before entering a clinical trial', says Woods. He also says that replacing a faulty gene that has multiple effects in the body may prove much more problematic than replacing a gene with a single main role.
Mark Kay, a US gene therapist based at Stanford University says that 'the results are significant and need to be considered in the design of future gene therapies'. However, he also sees a continuing need for SCID trials for patients with no other treatment options, ScienceNOW reports. But UK researcher Adrian Thrasher told the Daily Telegraph newspaper that the data is 'very preliminary', and the effects could be down to 'artificially high levels of the gene in the animals'. Thrasher, who runs the X-SCID trial based at Great Ormond Street Hospital in London, added that 'certainly we and our colleagues have found no evidence for this effect'.