Researchers have established the cause of the leukaemia which developed in two young patients taking part in a pioneering gene therapy trial to treat the fatal 'baby-in-a-bubble' syndrome, severe combined immunodeficiency (X-SCID).
The trial at the Necker-Enfants Malades clinic in Paris was stopped last year due to the higher than expected number of cases of leukaemia amongst the eight children taking part. After three years of successful gene therapy for X-SCID, leukaemia occurred in the two youngest patients undergoing treatment.
The cases, along with the death of a patient in a trial in the USA in which an inhaled adenoviral vector-delivered gene therapy led to an inflammatory response in the lungs, led to a widespread halt on the conduct of gene therapy trials around the world.
The scientists reveal in the journal Science that in the cases of the two boys, the gene therapy corrected the faulty gene but also activated a cancer-causing gene called LMO2.
They suggest a number of factors that might explain why this occurred at a very much higher frequency than expected and that by modifying these factors, scientists will be able to deliver a gene therapy to treat X-SCID which has a much lower risk of causing leukaemia.
X-SCID is a genetic disease only found in boys and prevents the normal development of the immune system, forcing them to live in sterile conditions or risk picking up a life-threatening infection. The disease is caused by a single mutated gene and in the absence of a matched bone marrow donor there is no cure other than gene therapy.
"Cancer is a possible side effect of gene therapy, so any research which will help scientists to modify the treatment to reduce that risk is of great importance," said Dr Terry Rabbitts of the UK Medical Research Council's Laboratory of Molecular Biology, one of the scientists involved in the project.
"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 as X-SCID can only be treated if a matched bone marrow donor is available," he added.
Both children who developed leukaemia during the trial underwent treatment for their cancer with chemotherapy and bone marrow transplants. They are alive and well, and in complete clinical remission.