Drug resistance confounding prion therapeutics

Berry, David B.; Lü, Duo; Geva, Michal; Watts, Joel C.; Bhardwaj, Sumita; Oehler, Abby; Renslo, Adam R.; DeArmond, Stephen J.; Prusiner, Stanley B.; Giles, Kurt

doi:10.1073/pnas.1317164110

Cited by 123 publications

(208 citation statements)

References 47 publications

(58 reference statements)

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“…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). Similarly, IND24, although effective at prolonging the lifespan of RML-infected mice, also produced drug-resistant prions but had no effect in CJD-infected Tg mice (37). Our findings are distinct from such cases because they show that a compound with demonstrated, albeit transient, efficacy against a strain in one species acts to directly enhance prion replication in a different species and produce prions with altered biological properties without the prerequisite of generating drugresistant variants of the original strain.…”

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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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%

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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“…Small molecules, such as compound B (cpd-B), Anle-138b, and the 2-aminothiazoles, were capable of significantly extending the disease incubation period in both Tg and WT mice following challenge with prions (19,(35)(36)(37). However, an important observation that has emerged from these therapeutic studies is that the efficacy of anti-prion compounds is highly strain-specific.…”

Section: Assessing Prion Disease Therapeutics Using Mouse Modelsmentioning

confidence: 99%

“…However, an important observation that has emerged from these therapeutic studies is that the efficacy of anti-prion compounds is highly strain-specific. Compounds that were effective at extending the lives of Tg mice infected with mouse-passaged scrapie prions had no effect in Tg mice challenged with human CJD prions (37). Thus, going forward, it will be imperative to perform therapeutic efficacy experiments in Tg mice expressing human PrP that have been inoculated with human prions to assess any potential translational utility.…”

Section: Assessing Prion Disease Therapeutics Using Mouse Modelsmentioning

confidence: 99%

Mouse Models for Studying the Formation and Propagation of Prions

Watts

Prusiner

2014

Journal of Biological Chemistry

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Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.

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“…Mice receiving IND24 or IND81 showed no adverse effects even at the highest dose of 210 mg/kg/d. Subsequently, a full pharmacokinetic investigation of IND24 and IND81 in mice showed that IND24 prolonged the survival of mice infected with RML and ME7 prions from scrapie or prions from chronic wasting disease, but was ineffective against prions from MM1-and VV2-type sporadic CJD (Berry et al 2013). …”

Section: Ind Seriesmentioning

confidence: 99%