NR AUQV
AU Tagliavini,F.
TI Prion disease therapeutics: tetracyclic compounds in in vitro models, animal models, and patients with Creutzfeldt-Jakob disease
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-14
PT Konferenz-Vortrag
AB The prion diseases are fatal neurodegenerative disorders for which no effective treatment is available. A large number of molecules have been tested in an attempt to find therapeutic agents, but only a few classes of compounds showed any beneficial effect in in vivo and/or in vitro models. Studies from our group led to recognize that some tetracyclic compounds, such as iododoxorubicin and tetracyclines, are able to (i) interact with and revert the protease-resistance of PrPsc extracted from brain tissue of patients with all forms of CJD, cattle with BSE and rodents with experimental scrapie, (ii) reduce the infectivity titer in prion-contaminated material, and (iii) prolong survival of prion-infected animals. On this ground, a series of CJD patients observed at "Carlo Besta" Institute in the last five years received compassionate treatment with doxycycline at a daily oral dose of 100 mg from the time of diagnosis to death. The choice of this drug among others tetracyclic compounds effective in experimental models was based on the observation that doxyclycline has favorable kinetics, relatively good capacity to cross the blood-brain barrier, low toxicity and good tolerability even for prolonged administration. Indeed, no CJD patient chronically treated with this drug showed adverse secondary effects. The retrospective analysis revealed that the subjects treated with doxycycline (n=21) survived significantly longer than untreated patients (n=78); in particular, the survival time (median ± SE) was 13.0 ± 4 months in the former and 6.0 ± 0.7 months in the latter (Log Rank test: p<0.001). A significant difference was still present when the doxycycline-treated group was compared to an untreated group equivalent for sex, age at onset and codon 129 PRNP polymorphism (treated: 13.9 ± 3.8 months, untreated: 6.1 ± 0.5 months, p<0.01), which are major predictors of survival of CJD patients. This result, based on an open observation, will be verified in a randomized, double-blind study of doxycycline versus placebo that has been recently sponsored by the Italian Agency of Drug (AIFA). A positive outcome of this trial would activate similar studies in other neurodegenerative disorders due to protein misfolding such as Alzheimer's disease, since the effects of doxycycline seem to be dependent upon a direct interaction with abnormal protein conformers with an extensive beta-sheet conformation rather than with a specific amino acid sequence.
AD Fabrizio Tagliavini, National Neurological Institute "Carlo Besta", Milano, Italy
SP englisch
PO Deutschland
OR Tagungsband