1887

Abstract

Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.

Keyword(s): Anle138b , drug , prion , scrapie and therapy
Funding
This study was supported by the:
  • National Institutes of Health (Award P20-GM113132)
    • Principle Award Recipient: NotApplicable
  • National Institutes of Health (Award 5T32AI007519-22)
    • Principle Award Recipient: KathrynS. Beauchemin
  • National Institute of Neurological Disorders and Stroke (Award R01NS118796)
    • Principle Award Recipient: SurachaiSupattapone
  • National Institute of Neurological Disorders and Stroke (Award R01NS117276)
    • Principle Award Recipient: SurachaiSupattapone
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/content/journal/jgv/10.1099/jgv.0.001705
2021-12-14
2022-01-28
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