Key result
Guanabenz significantly prolonged the survival time of scrapie-infected transgenic mice by up to 19% (113 vs 95 days, p=0.0004) and promoted ovine PrPSc clearance in cell-based assays.
Why the study?
Does Guanabenz improve survival and promote PrPSc clearance in preclinical models of prion disease?
Does Guanabenz improve survival and promote PrPSc clearance in preclinical models of prion disease?
Effect estimate: 18 days delay
Absolute Event Rate: 113% vs 95%
p-value: p=0.0004
Guanabenz, an alpha2-adrenergic receptor agonist used for hypertension, exhibits in vivo antiprion activity and prolongs survival in a mouse model of prion disease.
Supports hypothesis generation for guanabenz repurposing in prion disease; leaves open translation to human efficacy.
BACKGROUND: Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the discovery of the in vivo antiprion activity of Guanabenz (GA), an agonist of alpha2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast prions using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrP(Sc) clearance in a cell-based assay. These effects are very specific as evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on alpha2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prolonging slightly but significantly the survival of treated animals. CONCLUSION/SIGNIFICANCE: GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based diseases. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases.
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Tribouillard‐Tanvier et al. (2008) studied Prion-based diseases. Guanabenz vs. Solvent (5% glucose) was evaluated on Mean survival time (18 days delay, p=0.0004). Guanabenz significantly prolonged the survival time of scrapie-infected transgenic mice by up to 19% (113 vs 95 days, p=0.0004) and promoted ovine PrPSc clearance in cell-based assays.
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