{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:54:24Z","timestamp":1790891664525,"version":"4.1.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R37NS125431"],"award-info":[{"award-number":["R37NS125431"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS117276"],"award-info":[{"award-number":["R01NS117276"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS118796"],"award-info":[{"award-number":["R01NS118796"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["P20-GM113132"],"award-info":[{"award-number":["P20-GM113132"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    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\n                    <jats:italic>in vivo<\/jats:italic>\n                    as well as a brain-penetrant compound that inhibits mutant PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    propagation\n                    <jats:italic>in vitro<\/jats:italic>\n                    . None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012087","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T13:23:40Z","timestamp":1711977820000},"page":"e1012087","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease"],"prefix":"10.1371","volume":"20","author":[{"given":"Daniel J.","family":"Walsh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy R.","family":"Rees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surabhi","family":"Mehra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E. C.","family":"Bourkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lech","family":"Kaczmarczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Stuart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walker S.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel C.","family":"Watts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9060-4550","authenticated-orcid":true,"given":"Surachai","family":"Supattapone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"key":"ppat.1012087.ref001","volume-title":"Prion biology and diseases.","author":"SB Prusiner","year":"2000"},{"issue":"11","key":"ppat.1012087.ref002","doi-asserted-by":"crossref","first-page":"4611","DOI":"10.1073\/pnas.91.11.4611","article-title":"Inherited prion diseases","volume":"91","author":"SB Prusiner","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"ppat.1012087.ref003","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/sj.ejhg.5201544","article-title":"Prion disease genetics","volume":"14","author":"S. Mead","year":"2006","journal-title":"Eur J Hum Genet"},{"key":"ppat.1012087.ref004","article-title":"Genetic Prion Disease.","author":"I Zerr","year":"1993","journal-title":"GeneReviews((R)). Seattle (WA)"},{"issue":"31","key":"ppat.1012087.ref005","doi-asserted-by":"crossref","first-page":"7672","DOI":"10.1021\/bi00245a003","article-title":"Secondary structure analysis of the scrapie-associated protein PrP 27\u201330 in water by infrared spectroscopy","volume":"30","author":"BW Caughey","year":"1991","journal-title":"Biochemistry"},{"issue":"10","key":"ppat.1012087.ref006","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1002\/pro.5560011014","article-title":"Purification and properties of the cellular prion protein from Syrian hamster brain","volume":"1","author":"KM Pan","year":"1992","journal-title":"Protein Sci"},{"issue":"6539","key":"ppat.1012087.ref007","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/376434a0","article-title":"First experimental transmission of fatal familial insomnia","volume":"376","author":"J Tateishi","year":"1995","journal-title":"Nature"},{"issue":"2","key":"ppat.1012087.ref008","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1212\/WNL.46.2.532","article-title":"Experimental transmission of Creutzfeldt-Jakob disease and related diseases to rodents","volume":"46","author":"J Tateishi","year":"1996","journal-title":"Neurology"},{"issue":"2","key":"ppat.1012087.ref009","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/mds.27562","article-title":"Anle138b modulates alpha-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy","volume":"34","author":"A Heras-Garvin","year":"2019","journal-title":"Movement disorders: official journal of the Movement Disorder Society"},{"issue":"44","key":"ppat.1012087.ref010","doi-asserted-by":"crossref","first-page":"E4160","DOI":"10.1073\/pnas.1317164110","article-title":"Drug resistance confounding prion therapeutics","volume":"110","author":"DB Berry","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"ppat.1012087.ref011","doi-asserted-by":"crossref","first-page":"e1008581","DOI":"10.1371\/journal.ppat.1008581","article-title":"Emergence of prions selectively resistant to combination drug therapy.","volume":"16","author":"CM Burke","year":"2020","journal-title":"PLoS Pathog.PubMed Central PMCID"},{"issue":"12","key":"ppat.1012087.ref012","doi-asserted-by":"crossref","first-page":"e1006045","DOI":"10.1371\/journal.ppat.1006045","article-title":"A Single Subcutaneous Injection of Cellulose Ethers Administered Long before Infection Confers Sustained Protection against Prion Diseases in Rodents.","volume":"12","author":"K Teruya","year":"2016","journal-title":"PLoS Pathog."},{"key":"ppat.1012087.ref013","first-page":"102","article-title":"Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice","author":"KS Beauchemin","year":"2021","journal-title":"The Journal of general virology"},{"issue":"5646","key":"ppat.1012087.ref014","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1126\/science.1090187","article-title":"Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis","volume":"302","author":"G Mallucci","year":"2003","journal-title":"Science"},{"issue":"6927","key":"ppat.1012087.ref015","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/nature01457","article-title":"Monoclonal antibodies inhibit prion replication and delay the development of prion disease","volume":"422","author":"AR White","year":"2003","journal-title":"Nature"},{"issue":"1","key":"ppat.1012087.ref016","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1124\/jpet.115.224659","article-title":"Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains","volume":"355","author":"K 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Kim","year":"2013","journal-title":"Acta neuropathologica communications"},{"issue":"3","key":"ppat.1012087.ref023","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s12013-013-9663-z","article-title":"In silico analysis of prion protein mutants: a comparative study by molecular dynamics approach","volume":"67","author":"CG Doss","year":"2013","journal-title":"Cell Biochem Biophys"},{"issue":"5","key":"ppat.1012087.ref024","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1021\/bi501495j","article-title":"Requirements for mutant and wild-type prion protein misfolding in vitro","volume":"54","author":"GP Noble","year":"2015","journal-title":"Biochemistry"},{"key":"ppat.1012087.ref025","doi-asserted-by":"crossref","first-page":"e0167222","DOI":"10.1128\/jvi.01672-22","article-title":"Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease","volume":"2023","author":"SM Vallabh","year":"2023","journal-title":"J Virol"},{"key":"ppat.1012087.ref026","first-page":"2023","author":"S Mehra","year":"2023","journal-title":"Convergent generation of atypical prions in knock-in mouse models of genetic prion disease"},{"issue":"4","key":"ppat.1012087.ref027","doi-asserted-by":"crossref","first-page":"e0154604","DOI":"10.1371\/journal.pone.0154604","article-title":"Manipulating the Prion Protein Gene Sequence and Expression Levels with CRISPR\/Cas9.","volume":"11","author":"L Kaczmarczyk","year":"2016","journal-title":"PLoS One."},{"issue":"21","key":"ppat.1012087.ref028","doi-asserted-by":"crossref","first-page":"9558","DOI":"10.1128\/JVI.01106-16","article-title":"Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions","volume":"90","author":"JC Watts","year":"2016","journal-title":"J 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Giles","year":"2017","journal-title":"Cold Spring Harb Perspect Med."},{"issue":"6","key":"ppat.1012087.ref036","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00401-013-1114-9","article-title":"Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson\u2019s disease","volume":"125","author":"J Wagner","year":"2013","journal-title":"Acta Neuropathol"},{"issue":"4","key":"ppat.1012087.ref037","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1007\/s11095-012-0912-4","article-title":"Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice","volume":"30","author":"BM Silber","year":"2013","journal-title":"Pharm Res"},{"key":"ppat.1012087.ref038","doi-asserted-by":"crossref","first-page":"104021","DOI":"10.1016\/j.ebiom.2022.104021","article-title":"Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial.","volume":"80","author":"J Levin","year":"2022","journal-title":"EBioMedicine."},{"issue":"4","key":"ppat.1012087.ref039","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1007\/s12035-018-1228-0","article-title":"IVIG Delays Onset in a Mouse Model of Gerstmann-Straussler-Scheinker Disease","volume":"56","author":"H Gu","year":"2019","journal-title":"Mol Neurobiol"},{"issue":"36","key":"ppat.1012087.ref040","doi-asserted-by":"crossref","first-page":"12396","DOI":"10.1523\/JNEUROSCI.6189-11.2012","article-title":"Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Straussler-Scheinker disease","volume":"32","author":"CJ Cortes","year":"2012","journal-title":"J Neurosci"},{"key":"ppat.1012087.ref041","article-title":"Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease.","author":"K Qin","year":"2019","journal-title":"The Journal of general virology"},{"issue":"32","key":"ppat.1012087.ref042","doi-asserted-by":"crossref","first-page":"10072","DOI":"10.1523\/JNEUROSCI.2542-09.2009","article-title":"A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP","volume":"29","author":"W Yang","year":"2009","journal-title":"J Neurosci"},{"issue":"Pt 3","key":"ppat.1012087.ref043","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1099\/vir.0.007930-0","article-title":"Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins","volume":"90","author":"EA Asante","year":"2009","journal-title":"The Journal of general virology"},{"issue":"6","key":"ppat.1012087.ref044","doi-asserted-by":"crossref","first-page":"e3000725","DOI":"10.1371\/journal.pbio.3000725","article-title":"Spontaneous generation of prions and transmissible PrP amyloid in a humanised 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Minikel","year":"2020","journal-title":"Nucleic acids research"},{"issue":"16","key":"ppat.1012087.ref051","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.131175","article-title":"Antisense oligonucleotides extend survival of prion-infected mice.","volume":"5","author":"GJ Raymond","year":"2019","journal-title":"JCI Insight."}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012087","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T13:24:12Z","timestamp":1711977852000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012087"}},"subtitle":[],"editor":[{"given":"Suzette 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