ROLLER COASTER is the only phrase for it. Soon after “patient X” was born he was diagnosed as lacking vital immune defences due to a life-threatening genetic mutation. Six months later a pioneering treatment corrected the genetic defect and doctors pronounced him cured. Now, in a cruel reversal of fortune, the boy has leukaemia and is at the centre of the latest international row about the safety of gene therapy.
Scientists and doctors are scrambling to digest the implications of last week’s shock announcement that implanting the child with cells containing a healthy form of a defective gene may have led to his cancer. But already a confusing rift has opened up between the experts overseeing trials of the therapy in Britain and their counterparts in France and the US.
British regulators say the potential benefits of the treatment are so great it would unethical to break off ongoing trials. French and American experts insist the only ethical course is to halt trails while scientists investigate whether the treatment really is responsible for the boy’s leukaemia.
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They cannot both be right. But what is clear is that the illness – and the split over how to proceed – couldn’t have come at a worse time for gene therapists.
Long touted as the revolutionary key to treating inherited illnesses, gene therapy had only just recovered from the storm of criticism that followed the death of American teenager Jesse Gelsinger in the trial of a different type of gene therapy in 1999. Worse, the very treatment now being linked to leukaemia has been instrumental in restoring confidence, having produced a string of spectacular cures for other children suffering from “severe combined immunodeficiency”.
When Rhys Jones, one of four boys apparently cured by the therapy at Great Ormond Street Hospital in London, reached his second birthday just days before the leukaemia news broke, his mother described it as “a miracle”.
The disease, known as X-SCID, is linked to a gene on the X chromosome and leaves boys without any T cells, a type of white blood cell crucial to the immune system. The boys fall prey to even minor infections, and unless treated they normally die before their first birthday. Alain Fischer and his colleagues at the Necker Hospital in Paris treated patient X and 10 others like him by taking bone marrow from their bodies and infecting it with a retrovirus carrying a normal copy of the defective gene. Stem cells in the bone marrow that took up the gene were then grown in culture and returned to the boy.
After his treatment, doctors pronounced the boy cured and everything went well until he was two-and-a-half, when he contracted chickenpox. His white blood cell count soared to fight off the infection but never subsided afterwards. The cells continued to divide and he is now undergoing chemotherapy for leukaemia. “I think this event is directly linked to the gene therapy,” Fischer told 91av.
The French authorities stopped the trial immediately, and within hours the US Food and Drug Administration followed suit, halting three trials that were using retroviruses to insert genes. But in Britain, the government’s Gene Therapy Advisory Committee (GTAC) voted to continue trials at Great Ormond Street.
British experts argue that children with X-SCID would die if trials were stopped during the 12 to 18 months needed for the French investigation. They also say that leukaemia has always been regarded as a possible side effect of using retroviruses to genetically manipulate white blood cells, and that doctors in Britain made every effort to inform parents of the risk before any boys received the treatment.
“In balancing the potential risks and benefits to these children we have decided it is ethically justifiable to go ahead,” Norman Nevin, chairman of GTAC and a medical geneticist at Queen’s University Belfast, told reporters last week.
Not so, insists Arthur Caplan, one of the US’s best known bioethicists at the University of Pennsylvania Medical School in Philadelphia. “You have to weigh the risks and benefits, and for some, leukaemia is a risk worth taking,” he told 91av. “But to go ahead with trials not understanding exactly why leukaemia has arisen could turn risk into disaster.”
Yet even advocates of a moratorium see the swiftness of the American response as evidence of a “gun-shy” attitude to gene therapy among officials. The public uproar following Jesse Gelsinger’s death forced a complete reappraisal of the procedures, safety and scope of gene therapy. Gelsinger was being treated for a liver disorder, using an adenovirus similar to those that trigger common colds. Although the cause of his death was and still is a mystery, the shock burst gene therapy’s bubble, dispelling much of the hype that had surrounded it.
But even after this second major setback, nobody is about to throw in the towel. “We’re on a learning curve and need to persevere with these methods,” says Joseph Glorioso of the American Society of Gene Therapy.
And despite patient X’s leukaemia, the clear benefits of the therapy in other cases will galvanise the best minds in the world to think of how to get round the problem, says Savio Woo, a gene-therapy expert at Mount Sinai School of Medicine in New York City. Woo supports a temporary moratorium but calls on people to get the situation in perspective. “Ten out of 11 patients responding is a miracle,” he says.