CJD: The promise of treatment

reutzfeldt Jakob Disease (KJD) is always progressive. often rapidly so. and uniformly fatal. Intriguingly and confusingly, it exists in sporadididiopathic. inherited and acquired forms. While rare, it attracted extraordinary scientific. popular. political and media interest following the identification of variant CjD (or 'human bovine spongiform encephalopathy (BSE)') in 1996. It is an extremely distressing experience for relatives to watch the progression of this terrible disorder. and clinical neurologists have had to accept once more their impotence in the face of inexorable cerebral degeneration. Against this background. the Mail on Sunday reported a 'medical miracle' cure in August 200 I. following improvement in an individual treated with a drug in the US. Understandably, there were two broad types of reaction. On the one hand, some urged great caution, perhaps with some weariness born of previous experience with media 'cure' stories. On the other hand, there was great excitement with immediate demand for similar treatment to be provided in the UK The particular drug that led to this news story is a known, relatively toxic antimalarial called quinacrine. which has been superseded by more effective and less toxic antimalarials. Stanley Prusiner's group in San Francisco have published encouraging results of experimental work with quinacrine. chlorpromazine and related compounds (Korth et al. 2001). However, their impressive demonstration of the disappearance of PrP" (the disease-related form of prion protein) was in neuroblastoma cells infected with a strain of mouse-adapted scrapie. In other words, in cell cultures, not humans, with a laboratory prion disease, not CJD itself. The UK Department of Health reacted swiftly to this reported promise, ensuring that clinicians were aware of the situation and able to prescribe quinacrine on a voluntary 'named-patient' basis. An 'open' drug treatment trial was rapidly instituted and there are plans for a more formal trial of quinacrine. The results of treatment in individuals to date are not in the public domain. but there have been no more reports of dramatic improvement. It should be emphasised that quinacrine is simply one of a number of candidate treatments that need assessment. For example. in 1995. a non-opiate analgesic. flupirtine. was reported to be neuroprotective in prion-infected cell cultures and is being assessed in Germany (Perovic et al. 1995). So. where are we now with potential treatment for CJD? Intensive research has increased understanding of the molecular mechanisms underlying the disease. The conversion of a normal cellular protein (PrP3 to an abnormal form (PrP"). with the resultant accumulation of PrPk and amyloid formation is central to the disease process. Research has therefore particularly concentrated on compounds that disrupt these molecular events. Reduction of PrPz synthesis, prevention of PrP' conversion to PrPk. the prevention of PrP amyloid formation. the removal of accumulated PrPk and the prevention of any PrPQ toxicity have al l been considered bases for treatment. Many compounds have possible effects, but i t is a significant leap from biochemical theory and in vitro or cell-culture experiments to the treatment of an intact animal or human with disease. There are potential problems with clinical efficacy. toxicity and the ability of drugs to cross the blood-brain barrier. In addition, the pathogenesis of CjD is not completely understood. For example. reducing PrP' production would not be wise if depletion of P r P is itself harmful. However, the increasing scientific understanding of CJD provides the foundation for the design and initial evaluation of pharmacological therapies. Knowledge can breed hope. Of course, 'designer' drugs do not always fulfil their promise. It is wise for clinicians not to be blinded by the bright light of molecular medicine. Many very successful treatments have been discovered by accident and the initially proposed mechanisms underpinning useful therapies are not always confirmed. Even when success is achieved in animal experiments. it may not be reasonable to extrapolate from results in mice to humans. This is not only because of inter-species differences, but also because such experiments use specific strains of transmissable spongiform encephalopathy agent. There is some evidence that potential therapeutic agents may have differential effects in different forms of prion disease. For a clinician. a patient and their relatives. the real proof of therapeutic worth will come from observed sustained improvement in a human being with CJD. In the past, a variety of theoretically interesting compounds, including dapsone and amphotericin B. have proved ineffective in clinical settings. There are two general therapeutic circumstances to be considered. Firstly. there is treatment of established disease where there is evident and progressive neuronal degeneration and. by the time of diagnosis. there may already be irreversible neuropathological changes. Successful treatment would probably require early diagnosis. However. given the inevitable and usually rapid progression of CJD. the assessment of any real, useful therapeutic effect should be relatively easy. This is, in one sense, fortunate given the rarity of CJD. it would be difficult to organise the large-scale studies necessary in less uniform conditions like multiple sclerosis. Also. given the inevitably fatal nature of CJD. one might contemplate treatments of uncertain or even known toxicity, as with quinacrine. Secondly. there is the possibility of prophylactic treatment in those at particular risk of developing CJD. For example. individuals with a known PKNP (the prion protein gene) mutation or who have been exposed to a known risk such as human growth hormone. In such individuals. a reliable pre-symptomatic test would be invaluable. However. no such test exists and it is difficult to see how a potential test could be quickly validated. Any 'positive' results could be confirmed only by the eventual development of disease and 'negative' tests accepted only after lengthy follow-up. In addition, any truly prophylactic treatment should have low or no toxicity. Pentosan polysulphate has proved useful in delaying or even preventing scrapie infection in mice (Diringer and Ehlers. I99 I), but i ts efficacy partially depends on administration close to the time of infection. which is not known in many circumstances. Treatments may have symptomatic effects that can give rise to false hopes of curative actions. Indeed. quinacrine has properties that could conceivably lead to temporary clinical changes aside from any postulated effect on prion pathogenesis. Of course. symptomatic effects may be valued by patients and relatives, simply because any improvement is welcome. In conclusion. there is emerging real hope that increasing understanding of CJD mechanisms has led to the identification and development of potential treatments. and will lead to further ones. There is at present no proven evidence of actual treatment benefit in clinical settings. However quinacrine and other potential therapies will be formally tested in the near future and it should be possible to ascertain fairly quickly any significant and useful efficacy using relatively simple clinical assessments.