US and European scientists have published results confirming that a gene therapy technique triggered leukaemia in two boys taking part in a trial at the Necker hospital, Paris. Their findings, which appear in Science, show that the virus used to deliver the therapeutic gene activated a cancer-causing gene. Eleven boys with X-linked severe combined immune deficiency (X-SCID) underwent experimental gene therapy treatment at the French hospital, but the trial was halted in October 2002, after one of the boys developed leukaemia symptoms. When a second patient developed leukaemia, in January 2003, similar trials in several countries were suspended. Most, including one at London's Great Ormond Street Hospital, have now resumed, but only for patients with no other treatment options.
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. To carry out the gene therapy treatment, the French researchers harvested bone marrow from the patients, from which they isolated blood stem cells. They then infected these cells with a retrovirus (a virus that inserts its genetic material into the host cell's DNA) carrying a working gene, before returning the modified cells back to the patients.
Ten patients initially responded well to the treatment, but two later developed leukaemia: cancer of the bone marrow. In both cases, researchers found that the retrovirus had inserted its genetic material close to the 'on-switch' of a cancer-causing gene called LMO2. It is thought that this event caused the unregulated growth of the bone marrow cells, which in turn triggered the leukaemia, although other factors could have been involved. The two boys are reported to have responded well to chemotherapy and bone marrow transplant treatment, and are now in remission. Doctors at Great Ormond Street Hospital have successfully treated five SCID patients, including toddler Rhys Evans, using a very similar technique to that in the French trial. Despite the risks of gene therapy, many scientists say it is still the best option for some patients: 'Although it is anguishing for parents to expose their children to the chance of developing cancer, the benefits of gene therapy for this devastating disease greatly outweigh the risks of the disease itself' said Terry Rabbitts of the UK's MRC Laboratory of Molecular Biology, who helped investigate the French cancer cases.
Commenting on the new study, David Williams and Christopher Baum wrote in a Science article that 'it would be unrealistic not to expect gene therapies to produce side effects'. Doctors at the Necker Hospital are now working on ways of making the treatment safer - treating only older children, injecting fewer modified bone marrow cells, or using different viruses to deliver the gene could all help reduce the risks. 'The bottom line is that gene therapy works, there is no question about that. It works too well to stop trying it' said team leader Alain Fischer.