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Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.
Walsh, Daniel J; Rees, Judy R; Mehra, Surabhi; Bourkas, Matthew E C; Kaczmarczyk, Lech; Stuart, Erica; Jackson, Walker S; Watts, Joel C; Supattapone, Surachai.
Affiliation
  • Walsh DJ; Department of Biochemistry and Cell Biology Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
  • Rees JR; Department of Epidemiology Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
  • Mehra S; Department of Community and Family Medicine Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
  • Bourkas MEC; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
  • Kaczmarczyk L; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
  • Stuart E; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  • Jackson WS; Wallenberg Center for Molecular Medicine, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • Watts JC; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
  • Supattapone S; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
PLoS Pathog ; 20(4): e1012087, 2024 Apr.
Article in En | MEDLINE | ID: mdl-38557815
ABSTRACT
Prion diseases uniquely manifest in three distinct forms inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prions / Creutzfeldt-Jakob Syndrome / Prion Diseases Limits: Animals Language: En Journal: PLoS Pathog Year: 2024 Type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prions / Creutzfeldt-Jakob Syndrome / Prion Diseases Limits: Animals Language: En Journal: PLoS Pathog Year: 2024 Type: Article Affiliation country: United States