Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.
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). Alt...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-04-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012087&type=printable |
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| author | Daniel J Walsh Judy R Rees Surabhi Mehra Matthew E C Bourkas Lech Kaczmarczyk Erica Stuart Walker S Jackson Joel C Watts Surachai Supattapone |
| author_facet | Daniel J Walsh Judy R Rees Surabhi Mehra Matthew E C Bourkas Lech Kaczmarczyk Erica Stuart Walker S Jackson Joel C Watts Surachai Supattapone |
| author_sort | Daniel J Walsh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc72e3d470f04611b70c93e0829e5d34 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-bc72e3d470f04611b70c93e0829e5d342024-11-15T05:30:47ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-04-01204e101208710.1371/journal.ppat.1012087Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.Daniel J WalshJudy R ReesSurabhi MehraMatthew E C BourkasLech KaczmarczykErica StuartWalker S JacksonJoel C WattsSurachai SupattaponePrion 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012087&type=printable |
| spellingShingle | Daniel J Walsh Judy R Rees Surabhi Mehra Matthew E C Bourkas Lech Kaczmarczyk Erica Stuart Walker S Jackson Joel C Watts Surachai Supattapone Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. PLoS Pathogens |
| title | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. |
| title_full | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. |
| title_fullStr | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. |
| title_full_unstemmed | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. |
| title_short | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. |
| title_sort | anti prion drugs do not improve survival in novel knock in models of inherited prion disease |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1012087&type=printable |
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