{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:59:03Z","timestamp":1790787543070,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010728","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 NS125255"],"award-info":[{"award-number":["R01 NS125255"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Prion Alliance"},{"DOI":"10.13039\/100013114","name":"Broad Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013114","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015834","name":"Ono Pharma Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015834","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Anonymous Organization"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene (\n                    <jats:italic>PRNP<\/jats:italic>\n                    ). While no disease-modifying therapy is currently available, genetic and pharmacological proofs of concept support development of therapies that lower PrP levels in the brain. In light of proposals for clinical testing of such drugs in presymptomatic individuals at risk for genetic prion disease, extensive nonclinical data are likely to be required, with extra attention paid to choice of animal models. Uniquely, the entire prion disease process can be faithfully modeled through transmission of human prions to non-human primates (NHPs), raising the question of whether NHP models should be used to assess therapeutic efficacy. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. Using this dataset, we assess prion strain, route of administration, endpoint, and passage number to characterize the relationship of tested models to currently prevalent human subtypes of prion disease. We analyze the incubation times observed across diverse models and perform power calculations to assess the practicability of testing prion disease therapeutic efficacy in NHPs. We find that while some models may theoretically be able to support therapeutic efficacy studies, pilot studies would be required to confirm incubation time and attack rate before pivotal studies could be designed, cumulatively requiring several years. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. Our findings indicate that it would be challenging to conduct efficacy studies in NHPs in a paradigm that honors the potential advantages of NHPs over other available models, on a timeframe that would not risk unduly delaying patient access to promising drug candidates.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010728","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T13:39:06Z","timestamp":1661175546000},"page":"e1010728","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Analysis of non-human primate models for evaluating prion disease therapeutic efficacy"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-0831","authenticated-orcid":true,"given":"Meredith A.","family":"Mortberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Vallabh","family":"Minikel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-2702","authenticated-orcid":true,"given":"Sonia M.","family":"Vallabh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"ppat.1010728.ref001","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"SB Prusiner","year":"1998","journal-title":"PNAS"},{"key":"ppat.1010728.ref002","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1146\/annurev-genet-120213-092352","article-title":"Genetic Factors in Mammalian Prion Diseases","volume":"53","author":"S Mead","year":"2019","journal-title":"Annu Rev 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scrapie","volume":"73","author":"H B\u00fceler","year":"1993","journal-title":"Cell"},{"key":"ppat.1010728.ref010","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/j.1460-2075.1996.tb00467.x","article-title":"Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie","volume":"15","author":"M Fischer","year":"1996","journal-title":"EMBO J"},{"key":"ppat.1010728.ref011","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00401-017-1670-5","article-title":"Prion disease: experimental models and reality","volume":"133","author":"S Brandner","year":"2017","journal-title":"Acta Neuropathol"},{"key":"ppat.1010728.ref012","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S1474-4422(19)30403-X","article-title":"Towards a treatment for genetic prion disease: trials and biomarkers","volume":"19","author":"SM Vallabh","year":"2020","journal-title":"The Lancet 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membrane components of human brain during the span of adult human life of Swedes","volume":"94","author":"L Svennerholm","year":"1997","journal-title":"Acta Neuropathol"},{"key":"ppat.1010728.ref045","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1177\/0192623311436180","article-title":"Technical guide for nervous system sampling of the cynomolgus monkey for general toxicity studies","volume":"40","author":"ID Pardo","year":"2012","journal-title":"Toxicol Pathol"},{"key":"ppat.1010728.ref046","first-page":"219","article-title":"A Record of the Body Weight and Certain Organ and Gland Weights of 3690 Animals","volume":"40","author":"G Crile","year":"1940","journal-title":"Ohio Journal of Science"},{"key":"ppat.1010728.ref047","doi-asserted-by":"crossref","first-page":"e0168324","DOI":"10.1371\/journal.pone.0168324","article-title":"An Assessment of the Population of Cotton-Top Tamarins (Saguinus oedipus) and Their Habitat in Colombia","volume":"11","author":"A Savage","year":"2016","journal-title":"PLoS One"},{"key":"ppat.1010728.ref048","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aag0481","article-title":"Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy","volume":"9","author":"SL DeVos","year":"2017","journal-title":"Sci Transl Med"},{"key":"ppat.1010728.ref049","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.1172\/JCI99081","article-title":"Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models","volume":"128","author":"A McCampbell","journal-title":"J Clin Invest"},{"key":"ppat.1010728.ref050","article-title":"Targeting Huntingtin Expression in Patients with Huntington\u2019s Disease","author":"SJ Tabrizi","year":"2019","journal-title":"New England Journal of Medicine"},{"key":"ppat.1010728.ref051","doi-asserted-by":"crossref","first-page":"e1001342","DOI":"10.1371\/journal.pgen.1001342","article-title":"A 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