Analysis: Medical Research: Doctors Struggle with the Ethical Dilemma of Gene Therapy ; despite Controversy and Setbacks, the Pioneering Treatment for Congenital Disorders Remains a Prime Goal of Medical Researchers

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RHYS EVANS plays like any healthy toddler, having recently celebrated his second birthday. Yet little more than a year ago his parents were unsure he would reach his first. Rhys was born with an inherited disease that left him without an immune system.

The standard treatment is to find a sibling whose bone marrow can be transplanted, so the healthy cells can multiply and spark off the immune system. But Rhys has no siblings, and even that has only a one in three chance of effecting a cure. Non-family donors can provide marrow, but the success rate is even lower, and the side- effects can be serious.

Rhys, however, was lucky. He was successfully given gene therapy by a team at Great Ormond Street Children's Hospital. They extracted some of his bone marrow, used a harmless virus to add working immune system genes to the DNA of those faulty cells, and reimplanted it a few days later. The effects were dramatic. Since then, three other people in the UK with the disease - called X-SCID, or X-linked severe combined immune deficiency - have been successfully treated by the gene therapy team. "Gene therapy was our only real hope," Rhys's mother, Marie, said yesterday. "It has saved Rhys's life."

In France, 11 children with X-SCID have received gene therapy treatment since 1999. All had been well; the future looked promising.

But on 16 September came the news that some had feared. Doctors at the Necker hospital in Paris announced that a three-year-old who had received the gene therapy when six months old had developed leukaemia. And the virus used to insert the working genes into his DNA was blamed. The French have halted gene therapy trials to treat X-SCID pending a full investigation. But in Britain, the trials and treatments of boys like Rhys (the disease only affects boys, while girls can be carriers) will go on.

"It's an ethical dilemma," said Professor Norman Nevin, who chairs the Gene Therapy Advisory Council which met in urgent session yesterday to consider the ramifications of the French case. "The [French] investigation into what happened will take 12 to 18 months. During that time, one could be faced with the situation where you're presented with children with this illness who don't have a bone marrow match, who could die in two to three years.

"To deny gene therapy to them would be unethical, provided the parents are cognisant of the associated risks."

Doctors already think they know why the French case occurred and they are hopeful, even confident, that it is not part of a pattern.

The reason is that precisely where the working genes are added is a lottery. The human genome of DNA is about three billion base pairs long, reckoned to contain about 35,000 genes. Much of it is apparently a sort of genetic wasteland, without any function we can discern. The virus, with its gene baggage, inserts itself pretty much randomly among the base pairs. The chances of it hitting any one gene are small, because the virus is only about 5,000 base pairs long - about 1/100th the size of the genome.

There is a chance that it could insert itself into a working gene, and deactivate it or create problems, said Bobby Gaspar, a consultant immunologist on the Great Ormond Street team. "Leukaemia is a finite risk of gene therapy trials. But this and a trial in Science with some mice which was a special case are the only known occurrences ... The chances are somewhere in the range of 1 in 10 million to 100 million."

This appears to have been one of those chances. The virus inserted itself near a gene known as "LmO2", which is important for generating blood cells. Leukaemia is cancer of the blood, so it seems that the virus may have turned on the LmO2 gene wrongly. The child is responding to chemotherapy.

This might look like another blow to gene therapy, which was hyped as the perfect means of curing almost any illness. …