• CREUTZFELDT-JAKOB DISEASE
• PRION

Compassionate use of doxycycline, a tetracycline antibiotic, in patients with Creutzfeldt-Jakob disease (CJD) revealed an increased survival of 4–7 months as compared with historical controls, a result not confirmed by a randomised, double blind, placebo-controlled trial.1 Is then therapy with doxycycline for patients with CJD over? The report of Assar et al2 on a single patient with variably protease-sensitive prionopathy (VPSPr),3 a rare subtype form of sporadic CJD, who received 4-year treatment with doxycycline at a relatively early stage of disease, suggests it is not and encourages novel studies on the use of doxycycline in prion diseases. The patient, who carried the commonly VPSPr-associated valine homozygosity at the polymorphic codon 129 of the prion protein (PrP) gene (PRNP),3 survived 72 months or more, which is about 1 year longer than the longest survival time in the same subgroup of so far described patients.3 Interestingly, brain pathology did not reveal the expected severe and widespread lesions usually occurring in long-lasting patients, suggesting a reduced neurotoxic effect of the disease-associated PrP (PrP^CJD) after doxycycline treatments and confirming the in vitro data that tetracyclines block neuronal losses induced by prion fibrils.4 The rationale for using doxycycline in patients with CJD comes from preclinical data, which showed that this group of antibiotics prolongs the incubation periods of rodents experimentally infected with prion strains.4 In experimental models of prion diseases, however, doxycycline, as with other antiprion drugs, shows good efficacy when given before onset of clinical signs, modest effect if any at disease onset and no effect late in the course of disease.5 Assar et al2 started treatment with doxycycline in a relatively early phase of disease confirming that early administration of anti-prion drugs might have some chance of therapeutic success. Although the interpretation of this report needs caution because based on a single patient with a rare subform of sporadic CJD, these data stimulate a few considerations. First, randomised clinical trials in CJD should enrol patients at early stage of disease. This is possible by using less stringent criteria for including patients in clinical trials than those for surveillance, such as the detection of PrP^CJD in the cerebrospinal fluid or nasal mucosa by the RT-QuIC amplification method in patients with early neurological symptoms.5 Second, whether survival is a valid end point for measuring the efficiency of innovative therapy in patients with CJD should be considered. The patient reported by Assar et al2 survived longer than expected but she was in a state of permanent akinetic mutism for about 4 years. This limited success is similar to what was reported in patients with variant CJD under intraventricular infusion of pentosan polysulfate confirming preclinical data on the low, if any, efficiency of antiprion drugs given after the appearance of clinical signs and questioning the rationale of observational or randomised trials with available antiprion drugs.5 Prevention is what we have so far achieved in experimental models of prion disease and preventive treatment, such as using doxycycline in healthy mutated PRNP carriers of fatal familial insomnia, is perhaps the only reasonable choice.6