Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

Geschwind, Michael D.; Kuo, Amy; Wong, K; Haman, Aissa; Devereux, G.; Raudabaugh, Benjamin; Johnson, David Y.; Torres-Chae, Charles C.; Finley, Ron; Garcia, Paul A.; Thai, Julie; Cheng, Hugo Q.; Neuhaus, John; Forner, Sven; Duncan, Jacque L.; Possin, Katherine L.; DeArmond, Stephen J.; Prusiner, Stanley B.; Miller, Bruce L.

doi:10.1212/wnl.0b013e3182a9f3b4

Cited by 129 publications

(93 citation statements)

References 34 publications

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“…Tragically, in no case did treatment provide discernible benefits (10)(11)(12)(13)(14)(15). Possibly related to this failure, studies in mice lacking the multiple drug resistant gene inoculated with RML prions and orally dosed with quinacrine resulted in selection and propagation of quinacrineresistant prions (28).…”

Section: Discussionmentioning

confidence: 99%

“…Based on initial reports of quinacrine's effects on mouse prion propagation in cell culture, a plethora of studies were designed to discern the mechanism of its presumed antiprion effects (19,20,(29)(30)(31)(38)(39)(40)(41)(42)(43)(44)(45), to assess its pharmacokinetics (21,36,42,46) and to derive similar compounds with improved antiprion efficacy (18,20,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). These studies continue to this day, despite multiple failed clinical studies in patients with human prion diseases (10)(11)(12)(13)(14)(15). The findings reported here force a reconsideration of current strategies to screen antiprion drugs.…”

Section: Discussionmentioning

confidence: 99%

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Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Along with a stream of evidence-based medicine, several clinical trials have recently been performed within a structured framework, including flupirtine trials in Germany (Otto et al 2004), quinacrine trials in the United Kingdom (Collinge et al 2009) and United States (Geschwind et al 2013), and doxycycline trials in Italy and France . Table 1 summarizes these clinical trials and their results, and each trial is described in detail in the following section.…”

Section: Historical Overview Of Medical Interventions For Cjdmentioning

confidence: 99%

“…This study concluded that there was no difference in mortality between the treated and untreated groups. Another clinical trial of quinacrine conducted in the United States from 2005 to 2009 in a double-blind, placebo-controlled, stratified-randomization manner concluded that quinacrine did not increase survival of sporadic CJD patients compared with the placebo (Geschwind et al 2013). …”

Section: Flupirtinementioning

confidence: 99%

Insights from Therapeutic Studies for PrP Prion Disease

Teruya

Doh‐ura

2016

Cold Spring Harb Perspect Med

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“…In our sporadic Creutzfeldt-Jakob disease trial of quinacrine, 2 we off ered open-label treatment to patients returning for their 2 month study visit because we were concerned that patients would not enrol if they were not eventually off ered active treatment. This turned out to be a weakness of our trial design, because the 2 month randomised phase might have been too short.…”

Section: -3mentioning

confidence: 99%

Doxycycline for Creutzfeldt-Jakob disease: a failure, but a step in the right direction

Geschwind

2014

The Lancet Neurology

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Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

Abstract: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.

Cited by 129 publications

References 34 publications

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Insights from Therapeutic Studies for PrP Prion Disease

Doxycycline for Creutzfeldt-Jakob disease: a failure, but a step in the right direction

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