Development of prophylactic and therapeutic anti-prion drugs for the patients at high risks

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In Japan, where iatrogenic Creutzfeldt-Jacob disease (CJD) or hereditary prion disease has occurred frequently, development of prophylaxis and therapeutics for prion diseases has been required. This research covered not only the basic research but also the clinical application of the therapeutic development, and the following points were clarified.1.Many anti-prion compounds were discovered by screening with prion-infected cells. About 20 effective quinoline-ring vhemicals including several clinical medicines were found. More than 80 effective compaunds from benzothiazole-related chemicals or Congo red-related chemicals were discovered, and some of them were effective not only as therapeutic drugs but also as prion imaging probes capable of detecting abnormal prion protein deposition in the brain, when administered peripherally in the disease animal models. Pentosan polysulfate (SPS) and heparin derivatives were also found to he remarkably effective. Especially SPS was the most benefic … More ial, when administered intracerebroventricularly into the diseased animals.On the one hand, interaction analyses between prion protein (PrP) and anti-prion chemicals revealed that most of the anti-prion chemicals exert their anti-prion activities by interacting directly with the PrP and thus inhibiting the abnormal conversion. Correlation between the interaction affinity and the anti-prion activity was demonstrated and thus wan possibly applied to high-throughput screening for anti-prion chemicals. Furthermore, it was shown that anti-prion activities of the anti-prion chemicals were dependent of infected cell types as well as pathogen strains.2.About SPS which showed the most beneficial effects in the animal models, after checking the safety of its continuous intracerebroventricular infusion in experimental animals, experimental treatment was carried out in one British patient with variant CJD. In spite of his advanced clinical stage, intracerebroventricular SPS administration demonstrated more outstanding effects than expected, and it did not show any adverse effects. The findings in the patient, together with the findings in the animals model experiments, indicate that this treatment can be also used to prevent high-risk people from prion diseases. Less