Analysis: 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

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.

The first treatment to use it came in September 1990. It was used in the US on Ashanthi DeSilva, four, who had a condition called ADA, which also affects the immune system. It appeared to work. Optimism about gene therapy rocketed but her long-term survival probably had more to do with the drugs she kept taking.

Hopes for gene therapy at that time were sky high, but the fervour dimmed when trials produced results that were at best equivocal and at worst negative. Britain's first gene-therapy operation came in 1993 – the year the advisory council was set up – on Carly Todd, when she was 17 months old. That proved disappointing, although Carly is doing well after conventional treatment and a bone-marrow transplant.

The low point was in September 1999, when 18-year-old Jesse Gelsinger from Arizona died four days after starting trials of a gene therapy treatment for an inherited metabolic disorder. The suspicion was that the virus used to carry the genes had reacted with other cells in his body; he showed the signs of a severe immune reaction.

In the ensuing investigations, American researchers were found to be under-reporting the "adverse events" (up to and including deaths) of gene therapy. In the US, funding dried up, and applications to use gene therapy slumped.

In the UK, the Gene Therapy Advisory Council made its own review of the evidence, deciding to allow researchers to persist in their pursuit of this holy grail. Even as the bad news was emerging about Mr Gelsinger, the trials were starting in France to treat X-SCID.

And now gene therapy is starting to come out of its long clinical exile, as a potential, and lasting treatment for illnesses where conventional therapies are limited or rely on donations that may never arrive. To date, there have been 636 completed, ongoing or pending gene therapy clinical trials worldwide. The method varies: sometimes the genes are injected into the body directly (as with Jesse andAshanthi), or sometimes, as with Rhys and the French children, by extracting cells, treating them and reinserting them.

The successes are starting to make their mark. "Five years ago, there were no successful gene therapies," said Dr Gaspar. "Now, we have cures. X-SCID was the first, but there have also been successes with ADA, where two children have been cured in Italy. These are the first steps to gene therapy for a wide range of diseases."

CONDITIONS IN THE QUEUE FOR THERAPY

X-linked SCID

Severe combined immunodeficiency (SCID) linked to defective genes on the X-chromosome is an inherited disorder affecting boys. These "bubble babies" lack certain specialised cells of the immune system, making them highly vulnerable to potentially lethal infections.

Haemophilia

A blood-clotting disorder which is also inherited and affects mostly boys. Gene therapy trials in the US have shown some patients being able to cut down on medication.

Chronic granulomatous disease

This is a group of rare, inherited disorders of the immune system which results in gene defects in cells called phagocytes, which protect against infections by engulfing invading bacteria and fungi. The first UK clinical trials of gene therapies were approved in 2001.

Cystic Fibrosis

The most common genetic disease of western Europeans, cystic fibrosis results in a build-up of sticky mucus in the airways and lungs. Researchers have had limited success with nasal sprays loaded with genetically-modified viruses or fatty droplets called liposomes that contain the correct version of the gene.

Genital organ cancers

Many cancers of the vulva and cervix are linked with the human papiloma virus, which causes genital warts. Gene therapy trials are trying to stimulate the body's immune system to attack these cancers using a genetically modified form of the vaccinia virus. UK approval was given in 2000.

Liver cancer

A trial at the Hammersmith Hospital in London aimed to introduce a tumour-suppressing gene called p53 into cancer cells in order to stem the spread of the liver tumour. A modified common cold virus was proposed but the hospital has since withdrawn its application for approval.