Back to the drawing board for CJD treatment

LONDON — National newspapers and TV like nothing better than a 'miracle cure'. And the story last summer of a young British woman who appeared to make an astonishing recovery from variant Creutzfeldt Jakob Disease (CJD), after being the first human guinea pig to try a new drug treatment (quinacrine and chlorpromazine), had all the right ingredients for the journalistic frenzy that followed.Rachel Forber, from Newton-le-Willows in Merseyside, was a happy, active young, former soldier who quickly declined to a bed-ridden invalid requiring constant care after developing the disease.Yet within three weeks of starting the quinacrine and chlorpromazine regime, doctors were reported that she was able to get out of bed, walk unaided and even swim without support. It was a remarkable transition which, the newspapers suggested, seemed to offer the first real hope that science might have got the better of this devastating disease.But the death on 2 December 2001 of 21-year-old Rachel has dealt a blow to these hopes and raised questions about whether any ground really has been gained in the battle to find an effective therapy for vCJD. The circumstances of her death have not been reported in detail bit it has been suggested she developed hepatic complications.The episode has also highlighted the immense difficulty of finding a treatment for a disease for which, as things stand, there is no accurate diagnosis. Currently, the only way of knowing for sure if someone has CJD is through a post mortem examination after the disease has already killed them. Instead, doctors have to rely on available evidence through symptoms (anxiety, depression withdrawal, behavioural change and numbness of the face and limbs) and medical history.Hence the publicity attracted by the US trial, pioneered by Stanley Prusiner, who won the 1997 Nobel prize for medicine for his work on prions — the infectious protein agents thought to cause brain diseases such as CJD. Prusiner and his team at University of California School of Medicine found two drugs — quinacrine, a malaria treatment and chlorpromazine, used for schizophrenia and other psychotic conditions — appeared to prevent prion molecules from changing into the form linked with vCJD.According to the prion theory, which remains controversial, these valuable proteins become disrupted by the presence of other 'rogue' prions which spread to humans via bovine spongiform encephalopathy (BSE) contaminated meat in the food chain. Protease—sensitive protein — or PrPc — which is a constituent of the normal cell membrane undergoes a dramatic change to form an insoluble pathogenic form of the prion protein — or PrPsc. This, in turn, induces more of the normal PrPc to form PrPsc — triggering a chain reaction that results in exponential production of the harmful prion protein.As the number of aberrant proteins increases, they spark the pathological changes that characterise CJD — spongiform change, gliosis and neuronal loss. But, the mechanism for this is still something of a mystery as the behaviour and manifestation of other transmissible spongiform encephalopathies are in keeping with the action of a virus-like agent, rather than a mutant prion.If the prion theory is correct, the drug combination pioneered by Prusiner could — on paper at least — offer some hope, not least because both drugs have the ability to penetrate the blood-brain barrier. This means they could potentially help to 'clear out' rogue prions from cells. In laboratory studies, mouse cells deliberately infected with prions and found that two drugs appeared to stop the prions from being corrupted by the presence of the infectious agent.In effect, the drugs were able to remove rogue prions infected cells — and keep them cleared out. But it's less clear whether they have the power to repair damaged cells as well. Only by transferring this success to human volunteers will Prusiner and his team determine whether the drugs — routinely available in the UK for other indications — would have the desired effect. A second patient given the drugs showed no sign of improvement whatsoever.Despite the setback of Rachel Forber's death, the UK Medical Research Council (MRC)is pressing ahead with plans for a trial involving one of the drugs — quinacrine. The Department of Health has asked it to fast-track the process of drawing up protocols for a trial that will provide robust data on the effect of the drug. The MRC is reluctant to say when such a trial might begin — or even what form it might take — but it's likely to be within the next few months. It said the death of Rachel Forber has not changed things because, as the patient of a US doctor, her personal medical circumstances are not available to British researchers. "We need a trial here to assess the risks and benefits of the treatment," said MRC spokeswoman Dawn Duncan. "We have received a draft protocol and it's going through the fast-track peer review process now. I don't know how long it will be but it's going to happen fairly quickly. "Given the nature of the disease it probably will not be a normal trial — it will have to be specially designed", she said.However speedy the MRC is in setting up the trial, the results themselves may take some time to collect. CJD remains a very rare disease and, as such, the number of cases needed to achieve statistical significance could take years to recruit.Initial UK human studies will be confined to quinacrine, with more animal studies on chlorpromazine possible. The drugs will be assessed separately first — to assess individual efficacy — before any plans to look at them in combination. "The sensible thing to do is to look at them as separate entities so we can assess their risks and benefits," explained Duncan.In the meantime, the UK Government's CJD Surveillance Unit is advising neurologists that they can only prescribe the drugs (quinacrine and chlorpromazine) on a named-patient basis, as neither one is licensed for the treatment of human prion diseases. The suggested treatment regime for quinacrine is 200 mg six hourly for five doses, followed by 100mg three times a day. It added that the dosage for chlorpromazine has not yet been ascertained.With the media hype over, and the death of Rachel Forber, a more realistic assessment is now beginning to emerge of last summer's 'miracle cure' for CJD. But it could be years before the potential of these drugs is clarified by clinical evidence.

Back to the drawing board for CJD treatment

The death of woman with CJD being treated with a novel drug combination casts doubts on the 'miracle cure' claim for the disease.

Interested in reading more?

Become a Member of