Washington

The revelation last week that experimental gene therapy may have given a child a cancer-like illness has provoked diverse regulatory responses around the world.

The child was involved in a trial to treat severe combined immunodeficiency disease (SCID), a condition that disrupts the early development of the immune system.

France and the United States immediately suspended all SCID gene-therapy trials, whereas Britain elected to continue enrolling and treating patients in its two studies. Germany, by contrast, had already suspended a wider range of 13 similar gene-therapy trials in June, following reports that the technique may cause cancer in mice.

The SCID patient is a three-year-old French boy taking part in a clinical trial run by gene-therapy pioneer Alain Fischer of the Necker Hospital for Sick Children in Paris. SCID is fatal if not treated by a bone-marrow transplant. But many children lack a perfectly matched donor, and of these about 30–40% who suffer from a particular form of SCID die.

Fischer's technique hinges on a gene for a receptor that triggers the normal development of cells in the immune system. He uses a retrovirus to ferry the corrective gene to bone-marrow cells, and has so far cured 10 children.

But routine checks revealed worrying signs that the boy, one of those 10, had developed a leukaemia-like illness. The incident could have wide implications for the troubled field of gene therapy, as Fischer's SCID treatment had been the field's greatest success to date.

The widely diverging reactions to the news highlight the difficulty of balancing the immediate risks posed by some clinical trials against their long-term potential benefits. In the United States, the Institute of Medicine has just proposed reforms in a bid to get the balance right (see page 546). And the US Food and Drug Administration (FDA) has called a meeting this week to discuss how to proceed with gene therapies for SCID and other diseases.

Clinical researchers attribute the varying responses to the French boy's condition to a multitude of cultural, political and scientific factors. French authorities are sensitive to the fact that the adverse event occurred there, and US regulators are acutely aware of questions that were raised after the death of 18-year-old Jesse Gelsinger in a gene-therapy trial three years ago. Germany, meanwhile, maintains a generally cautious approach to research on human subjects, whereas Britain tends to take a more permissive approach, in the hope that such research will yield major benefits.

“Different countries are taking slightly different positions — the British are being very open-minded and the Germans want to block everything,” says Fischer. At this point, he adds, it seems reasonable to halt gene-therapy trials that use retroviruses to target bone-marrow cells.

Retroviruses insert themselves randomly into DNA, but scientists have long worried that this activity has the potential to promote uncontrolled cell growth.

In the French child's case, Fischer says, the retroviral vector has inserted itself into a stretch of DNA that regulates the gene LMO2. This gene can cause leukaemia, and the boy's defective immune cells seem to be expressing LMO2. This raises the possibility that the retroviral vector activated the gene, leading to the boy's illness.

The suspension of German trials earlier this year followed a report that a retroviral gene therapy had caused leukaemia in mice (Z. Li et al. Science 296, 497; 2002). Christopher Baum, the study's principal investigator, who is currently at the Cincinnati Children's Hospital Medical Center, says that the German authorities will let the trials continue after doctors revise their informed-consent documents to tell patients about the risk of cancer.

Baum and his co-authors suspect that a particular marker gene used in their study played a part in causing leukaemia. Therefore, Baum and Fischer say, the Science finding by itself did not justify halting all trials that use retroviral vectors.

“Until now, this was a perfect therapy for SCID. Now there are risks,” says Don Kohn, a paediatrician at Children's Hospital of Los Angeles who was leading a gene-therapy trial for SCID. Kohn has treated four children, all of whom are still healthy, but the FDA has now suspended his trial.

Additional reporting by Quirin Schiermeier.