Researchers fear that GDNF might trigger a dangerous immune reaction in patients.

One of the most promising experimental therapies for Parkinson's disease could be shelved after scientists revealed today that a clinical trial has been stopped because of safety concerns.

During the treatment, a protein called glial-derived neurotrophic factor (GDNF) is drip-fed into the brains of patients with the movement disorder. The idea is that the protein will nourish dopamine-manufacturing brain cells, which shrivel up during the disease.

Hopes for the treatment soared last year when it was announced that the first five people treated with GDNF experienced a dramatic recovery in their movements¹. Scientists think the therapy is particularly exciting because it is one of the few that attempts to preserve or pep up fading brain cells, rather than simply treating the symptoms of the disease.

But on Tuesday, Anthony Lang of Toronto Western Hospital in Canada revealed that a second, more extensive clinical trial of GDNF has been halted because the drug showed little signs of working and some potentially dangerous side effects. Lang, who was one of the trial's lead investigators, discussed the results at the annual meeting of the American Neurological Association in Toronto.

The setback echoes disappointing results from another promising experimental therapy in 2003, when scientists found that implants of foetal brain tissue showed little effect in large trials. "[GDNF] was our remaining immediate hope," says William Langston, president of the Parkinson's Institute in Sunnyvale, California. "It's a very serious setback."

Danger signs

The pharmaceutical company Amgen, which sponsored the trial, announced in June that GDNF did not appear to have benefited patients after the first six months of the trial. But doctors continued to track patients who were receiving the drug, and Lang is the first to report the detailed results.

Of the 34 people in the study, four started producing antibodies to the GDNF protein, says Lang. Although the patients appeared healthy, this raises fears that the antibodies might go on to trigger a dangerous immune reaction if treatment had continued.

In addition, studies in monkeys have found that brain cells in two animals given GDNF began to break down. As a result, doctors took all patients off the therapy earlier this month. "It's been quite a blow to the field," says Lang.

There will be knock-on effects for several dozen research groups around the world who are developing alternative ways to deliver GDNF to patients' brains, using gene therapy or by implanting cells that secrete the protein, for example.

The biggest concern is that Amgen will lose interest completely. Because the company holds patents on GDNF, research into the molecule could grind to a halt. "If it falters, a lot of other things may fold," says Clive Svendsen of the University of Wisconsin, Madison, who was involved in the earlier five-patient trial.

Scientists have yet to explain the discrepancy between the earlier five-patient trial, which was performed in the UK, and the larger North American trial. It is possible that the improvement seen in the first set of patients was simply a placebo effect, because all of them knew that they were taking the treatment. By contrast, those in the second trial were randomly assigned to receive infusions of GDNF or a placebo, and they did not know which one they were taking.

Svendsen argues that there may be other explanations for the difference in results. For example, Lang's trial used smaller doses of GDNF and a larger plastic tube to feed the protein into the brain, which may have caused more damage. "We don't really feel it's been a fair comparison," he says.

In addition, brain scans carried out in both studies showed that dopamine-producing brain cells showed more signs of life than before the treatment. The researchers in the field now plan to meet up and discuss what to do next.

Until then, it is premature to sound the death knell for GDNF therapy, Langston argues, especially when there are few experimental therapies ready to take its place. "I'd hate to see it abandoned at this point," he says. "There's no sequel waiting in the wings." 

president of the Parkinson's Institute in Sunnyvale, California

• References

  1. Gill S. S., et al. Nature Medicine, 9. 589 - 595 (2003). | Article | PubMed | ISI | ChemPort |