{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:59:23Z","timestamp":1793239163377,"version":"4.5.0"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T00:00:00Z","timestamp":1597017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"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\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31 AI122592"],"award-info":[{"award-number":["F31 AI122592"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["GRFP 2015214731"],"award-info":[{"award-number":["GRFP 2015214731"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Prion Alliance"},{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that &amp;lt;25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.<\/jats:p>","DOI":"10.1093\/nar\/gkaa616","type":"journal-article","created":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T15:13:28Z","timestamp":1594653208000},"page":"10615-10631","source":"Crossref","is-referenced-by-count":154,"title":["Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints"],"prefix":"10.1093","volume":"48","author":[{"given":"Eric Vallabh","family":"Minikel","sequence":"first","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"},{"name":"Prion Alliance, Cambridge, MA, 02139, USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA\u00a002114, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA\u00a002114, USA"},{"name":"Harvard Medical School, Boston, MA\u00a002115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hien T","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals Inc, Carlsbad, CA\u00a092010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Le","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"O\u2019Moore","sequence":"additional","affiliation":[{"name":"McLaughlin Research Institute, Great Falls, MT\u00a059405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose","family":"Pitstick","sequence":"additional","affiliation":[{"name":"McLaughlin Research Institute, Great Falls, MT\u00a059405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Graffam","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A","family":"Carlson","sequence":"additional","affiliation":[{"name":"McLaughlin Research Institute, Great Falls, MT\u00a059405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Kavanaugh","sequence":"additional","affiliation":[{"name":"McLaughlin Research Institute, Great Falls, MT\u00a059405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasna","family":"Kriz","sequence":"additional","affiliation":[{"name":"Cervo Brain Research Center, Universit\u00e9 Laval, Qu\u00e9bec, QC G1J 2G3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae\u00a0Beom","family":"Kim","sequence":"additional","affiliation":[{"name":"PerkinElmer, Hopkinton, MA\u00a001748, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI\u00a049503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Wille","sequence":"additional","affiliation":[{"name":"University of Alberta, Edmonton, AB T6G 2M8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judd","family":"Aiken","sequence":"additional","affiliation":[{"name":"University of Alberta, Edmonton, AB T6G 2M8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"McKenzie","sequence":"additional","affiliation":[{"name":"University of Alberta, Edmonton, AB T6G 2M8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Doh-ura","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi\u00a0980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Beck","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"O\u2019Keefe","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn","family":"Stathopoulos","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Caron","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart L","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"},{"name":"Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA\u00a002138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B","family":"Carroll","sequence":"additional","affiliation":[{"name":"Western Washington University, Bellingham, WA\u00a098225, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly B","family":"Kordasiewicz","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals Inc, Carlsbad, CA\u00a092010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6248-6654","authenticated-orcid":false,"given":"Deborah\u00a0E","family":"Cabin","sequence":"additional","affiliation":[{"name":"McLaughlin Research Institute, Great Falls, MT\u00a059405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-2702","authenticated-orcid":false,"given":"Sonia M","family":"Vallabh","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA\u00a002142, USA"},{"name":"Prion Alliance, Cambridge, MA, 02139, USA"},{"name":"Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA\u00a002114, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA\u00a002114, USA"},{"name":"Harvard Medical School, Boston, MA\u00a002115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,8,10]]},"reference":[{"key":"2020110419231440600_B1","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"Prusiner","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B2","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":"Vallabh","year":"2020","journal-title":"Lancet Neurol."},{"key":"2020110419231440600_B3","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/0092-8674(93)90360-3","article-title":"Mice devoid of PrP are resistant to scrapie","volume":"73","author":"B\u00fceler","year":"1993","journal-title":"Cell"},{"key":"2020110419231440600_B4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13567-019-0731-2","article-title":"Goats naturally devoid of PrPC are resistant to scrapie","volume":"51","author":"Salvesen","year":"2020","journal-title":"Vet. Res."},{"key":"2020110419231440600_B5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/BF03403528","article-title":"High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene","volume":"1","author":"B\u00fceler","year":"1994","journal-title":"Mol. Med."},{"key":"2020110419231440600_B6","doi-asserted-by":"crossref","first-page":"10608","DOI":"10.1073\/pnas.90.22.10608","article-title":"Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies","volume":"90","author":"Prusiner","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B7","doi-asserted-by":"crossref","first-page":"7586","DOI":"10.1128\/JVI.69.12.7586-7592.1995","article-title":"Accumulation of proteinase K-resistant prion protein (PrP) is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent","volume":"69","author":"Sakaguchi","year":"1995","journal-title":"J. Virol."},{"key":"2020110419231440600_B8","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":"Fischer","year":"1996","journal-title":"EMBO J."},{"key":"2020110419231440600_B9","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":"Mallucci","year":"2003","journal-title":"Science"},{"key":"2020110419231440600_B10","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1099\/vir.0.80947-0","article-title":"Prion clearance in bigenic mice","volume":"86","author":"Safar","year":"2005","journal-title":"J. Gen. Virol."},{"key":"2020110419231440600_B11","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/356577a0","article-title":"Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein","volume":"356","author":"B\u00fceler","year":"1992","journal-title":"Nature"},{"key":"2020110419231440600_B12","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nbt1271","article-title":"Production of cattle lacking prion protein","volume":"25","author":"Richt","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"2020110419231440600_B13","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1297-9716-43-87","article-title":"Healthy goats naturally devoid of prion protein","volume":"43","author":"Benestad","year":"2012","journal-title":"Vet. Res."},{"key":"2020110419231440600_B14","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nature19312","article-title":"The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6","volume":"536","author":"K\u00fcffer","year":"2016","journal-title":"Nature"},{"key":"2020110419231440600_B15","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nn.2483","article-title":"Axonal prion protein is required for peripheral myelin maintenance","volume":"13","author":"Bremer","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2020110419231440600_B16","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1096\/fj.201902588R","article-title":"Demyelinating polyneuropathy in goats lacking prion protein","volume":"34","author":"Skedsmo","year":"2019","journal-title":"FASEB J."},{"key":"2020110419231440600_B17","doi-asserted-by":"crossref","first-page":"322ra9","DOI":"10.1126\/scitranslmed.aad5169","article-title":"Quantifying prion disease penetrance using large population control cohorts","volume":"8","author":"Minikel","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2020110419231440600_B18","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2267-z","article-title":"Evaluating drug targets through human loss-of-function genetic variation","volume":"581","author":"Minikel","year":"2020","journal-title":"Nature"},{"key":"2020110419231440600_B19","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1073\/pnas.93.6.2403","article-title":"Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus","volume":"93","author":"Lledo","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B20","doi-asserted-by":"crossref","first-page":"10238","DOI":"10.1073\/pnas.0802759105","article-title":"Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease","volume":"105","author":"White","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B21","doi-asserted-by":"crossref","first-page":"e11085","DOI":"10.1371\/journal.pone.0011085","article-title":"Liposome-siRNA-peptide complexes cross the blood-brain barrier and significantly decrease PrP on neuronal cells and PrP in infected cell cultures","volume":"5","author":"Pulford","year":"2010","journal-title":"PLoS One"},{"key":"2020110419231440600_B22","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1038\/mtna.2011.6","article-title":"Intracerebral infusion of antisense oligonucleotides into prion-infected mice","volume":"1","author":"Nazor\u00a0Friberg","year":"2012","journal-title":"Mol Ther Nucleic Acids"},{"key":"2020110419231440600_B23","doi-asserted-by":"crossref","first-page":"e98496","DOI":"10.1371\/journal.pone.0098496","article-title":"Convection-enhanced delivery of AAV2-PrPshRNA in prion-infected mice","volume":"9","author":"Ahn","year":"2014","journal-title":"PLoS One"},{"key":"2020110419231440600_B24","doi-asserted-by":"crossref","first-page":"e88797","DOI":"10.1371\/journal.pone.0088797","article-title":"Systemic delivery of siRNA down regulates brain prion protein and ameliorates neuropathology in prion disorder","volume":"9","author":"Lehmann","year":"2014","journal-title":"PLoS One"},{"key":"2020110419231440600_B25","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting Huntingtin Expression in Patients with Huntington's Disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"2020110419231440600_B26","first-page":"E533","article-title":"Safety, PK, PD, and exploratory efficacy in a single and multiple-dose study of a SOD1 antisense oligonucleotide (BIIB067) administered to participants with ALS","volume-title":"Neurology","author":"Miller","year":"2019"},{"key":"2020110419231440600_B27","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev-med-041217-010829","article-title":"Therapeutic antisense oligonucleotides are coming of age","volume":"70","author":"Bennett","year":"2019","journal-title":"Annu. Rev. Med."},{"key":"2020110419231440600_B28","doi-asserted-by":"crossref","first-page":"131175","DOI":"10.1172\/jci.insight.131175","article-title":"Antisense oligonucleotides extend survival of prion-infected mice","volume":"4","author":"Raymond","year":"2019","journal-title":"JCI Insight"},{"key":"2020110419231440600_B29","doi-asserted-by":"crossref","first-page":"12889","DOI":"10.1128\/JVI.01563-07","article-title":"Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner","volume":"81","author":"Kawasaki","year":"2007","journal-title":"J. Virol."},{"key":"2020110419231440600_B30","doi-asserted-by":"crossref","first-page":"E4160","DOI":"10.1073\/pnas.1317164110","article-title":"Drug resistance confounding prion therapeutics","volume":"110","author":"Berry","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B31","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1124\/jpet.113.205799","article-title":"Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice","volume":"347","author":"Lu","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2020110419231440600_B32","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":"Giles","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2020110419231440600_B33","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1124\/jpet.116.235556","article-title":"Optimization of aryl amides that extend survival in prion-infected mice","volume":"358","author":"Giles","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2020110419231440600_B34","doi-asserted-by":"crossref","first-page":"e1000673","DOI":"10.1371\/journal.ppat.1000673","article-title":"Continuous quinacrine treatment results in the formation of drug-resistant prions","volume":"5","author":"Ghaemmaghami","year":"2009","journal-title":"PLoS Pathog."},{"key":"2020110419231440600_B35","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1126\/science.1183218","article-title":"Darwinian evolution of prions in cell culture","volume":"327","author":"Li","year":"2010","journal-title":"Science"},{"key":"2020110419231440600_B36","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1093\/brain\/awh249","article-title":"Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies","volume":"127","author":"Pocchiari","year":"2004","journal-title":"Brain"},{"key":"2020110419231440600_B37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/acn3.378","article-title":"Extended and direct evaluation of RT-QuIC assays for Creutzfeldt-Jakob disease diagnosis","volume":"4","author":"Groveman","year":"2017","journal-title":"Ann Clin Transl Neurol"},{"key":"2020110419231440600_B38","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.1038\/s41598-017-10922-w","article-title":"High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions","volume":"7","author":"Franceschini","year":"2017","journal-title":"Sci. Rep."},{"key":"2020110419231440600_B39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13195-017-0331-1","article-title":"The CSF neurofilament light signature in rapidly progressive neurodegenerative dementias","volume":"10","author":"Abu-Rumeileh","year":"2018","journal-title":"Alzheimers Res Ther"},{"key":"2020110419231440600_B40","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1136\/jnnp-2017-317793","article-title":"Neurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt-Jakob disease, and tau correlates with rate of disease progression","volume":"89","author":"Thompson","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2020110419231440600_B41","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1001\/jamaneurol.2019.1071","article-title":"Association of blood and cerebrospinal fluid tau level and other biomarkers with survival time in sporadic Creutzfeldt-Jakob disease","volume":"76","author":"Staffaroni","year":"2019","journal-title":"JAMA Neurol."},{"key":"2020110419231440600_B42","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/ana.24833","article-title":"Diagnostic and prognostic value of human prion detection in cerebrospinal fluid","volume":"81","author":"Foutz","year":"2017","journal-title":"Ann. Neurol."},{"key":"2020110419231440600_B43","doi-asserted-by":"crossref","first-page":"e125","DOI":"10.1212\/WNL.0000000000007745","article-title":"Age at onset in genetic prion disease and the design of preventive clinical trials","volume":"93","author":"Minikel","year":"2019","journal-title":"Neurology"},{"key":"2020110419231440600_B44","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s12916-020-01608-8","article-title":"Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease","volume":"18","author":"Vallabh","year":"2020","journal-title":"BMC Med."},{"key":"2020110419231440600_B45","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1084\/jem.20151610","article-title":"Strictly co-isogenic C57BL\/6J-Prnp-\/- mice: a rigorous resource for prion science","volume":"213","author":"Nuvolone","year":"2016","journal-title":"J. Exp. Med."},{"key":"2020110419231440600_B46","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.neulet.2004.06.020","article-title":"Non-invasive imaging of GFAP expression after neuronal damage in mice","volume":"367","author":"Zhu","year":"2004","journal-title":"Neurosci. Lett."},{"key":"2020110419231440600_B47","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s003359900551","article-title":"Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment","volume":"8","author":"Rogers","year":"1997","journal-title":"Mamm. Genome"},{"key":"2020110419231440600_B48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/(SICI)1521-4036(199906)41:3<295::AID-BIMJ295>3.0.CO;2-2","article-title":"Proof of safety in toxicology based on the ratio of two means for normally distributed data","volume":"41","author":"Hauschke","year":"1999","journal-title":"Biometrical J."},{"key":"2020110419231440600_B49","article-title":"mratios: ratios of coefficients in the general linear model","author":"Djira","year":"2018"},{"key":"2020110419231440600_B50","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4757-3294-8","volume-title":"Modeling Survival Data: Extending the Cox Model Springer","author":"Therneau","year":"2000"},{"key":"2020110419231440600_B51","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1093\/biomet\/81.3.515","article-title":"Proportional hazards tests and diagnostics based on weighted residuals","volume":"81","author":"Grambsch","year":"1994","journal-title":"Biometrika"},{"key":"2020110419231440600_B52","doi-asserted-by":"crossref","first-page":"601","DOI":"10.2307\/2530904","article-title":"Confidence intervals for the survival function using Cox's proportional-hazard model with covariates","volume":"40","author":"Link","year":"1984","journal-title":"Biometrics"},{"key":"2020110419231440600_B53","doi-asserted-by":"crossref","first-page":"e0146021","DOI":"10.1371\/journal.pone.0146021","article-title":"Dose-response analysis using R","volume":"10","author":"Ritz","year":"2015","journal-title":"PLoS One"},{"key":"2020110419231440600_B54","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-pharmtox-010716-104846","article-title":"Pharmacology of antisense drugs","volume":"57","author":"Bennett","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2020110419231440600_B55","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2003715","article-title":"Phase 1\u20132 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS","volume":"383","author":"Miller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"2020110419231440600_B56","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/S0140-6736(61)92008-6","article-title":"Encephalopathy in mice produced by inoculation with scrapie brain material","volume":"1","author":"Chandler","year":"1961","journal-title":"Lancet"},{"key":"2020110419231440600_B57","doi-asserted-by":"crossref","first-page":"19841","DOI":"10.1074\/jbc.R114.550707","article-title":"Mouse models for studying the formation and propagation of prions","volume":"289","author":"Watts","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2020110419231440600_B58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/biom10010001","article-title":"Characterization of the prion protein binding properties of antisense oligonucleotides","volume":"10","author":"Reidenbach","year":"2019","journal-title":"Biomolecules"},{"issue":"Pt 3","key":"2020110419231440600_B59","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1099\/0022-1317-72-3-595","article-title":"The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis","volume":"72","author":"Bruce","year":"1991","journal-title":"J. Gen. Virol."},{"key":"2020110419231440600_B60","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S0368-1742(63)80018-1","article-title":"Further observations on the experimental transmission of scrapie from sheep and goats to laboratory mice","volume":"73","author":"Zlotnik","year":"1963","journal-title":"J. Comp. Pathol."},{"key":"2020110419231440600_B61","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1750-3639.1995.tb00577.x","article-title":"Inherited prion diseases and transmission to rodents","volume":"5","author":"Tateishi","year":"1995","journal-title":"Brain Pathol."},{"key":"2020110419231440600_B62","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1126\/science.1183748","article-title":"Generating a prion with bacterially expressed recombinant prion protein","volume":"327","author":"Wang","year":"2010","journal-title":"Science"},{"key":"2020110419231440600_B63","doi-asserted-by":"crossref","first-page":"299ra123","DOI":"10.1126\/scitranslmed.aab1923","article-title":"Structure-based drug design identifies polythiophenes as antiprion compounds","volume":"7","author":"Herrmann","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"2020110419231440600_B64","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neuron.2016.05.018","article-title":"Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases","volume":"91","author":"Bacioglu","year":"2016","journal-title":"Neuron"},{"key":"2020110419231440600_B65","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S1474-4422(17)30124-2","article-title":"Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis","volume":"16","author":"Byrne","year":"2017","journal-title":"Lancet Neurol."},{"key":"2020110419231440600_B66","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41591-018-0304-3","article-title":"Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease","volume":"25","author":"Preische","year":"2019","journal-title":"Nat. Med."},{"key":"2020110419231440600_B67","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/msb.2009.10","article-title":"A systems approach to prion disease","volume":"5","author":"Hwang","year":"2009","journal-title":"Mol. Syst. Biol."},{"key":"2020110419231440600_B68","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1073\/pnas.0907339106","article-title":"Measuring prions by bioluminescence imaging","volume":"106","author":"Tamg\u00fcney","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B69","doi-asserted-by":"crossref","first-page":"4999","DOI":"10.1128\/JVI.78.10.4999-5006.2004","article-title":"Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models","volume":"78","author":"Doh-ura","year":"2004","journal-title":"J. Virol."},{"key":"2020110419231440600_B70","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's disease","volume":"125","author":"Wagner","year":"2013","journal-title":"Acta Neuropathol."},{"key":"2020110419231440600_B71","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.3390\/ijms18051023","article-title":"Unraveling prion protein interactions with aptamers and other PrP-binding nucleic acids","volume":"18","author":"Macedo","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"2020110419231440600_B72","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1128\/AAC.50.3.1034-1044.2006","article-title":"Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides","volume":"50","author":"Kocisko","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"2020110419231440600_B73","doi-asserted-by":"crossref","first-page":"190","DOI":"10.2119\/2006-00073.Karpuj","article-title":"Phosphorothioate oligonucleotides reduce PrPSc levels and prion infectivity in cultured cells","volume":"13","author":"Karpuj","year":"2007","journal-title":"Mol. Med."},{"key":"2020110419231440600_B74","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1089\/nat.2018.0772","article-title":"Guidelines for experiments using antisense oligonucleotides and double-stranded RNAs","volume":"29","author":"Gagnon","year":"2019","journal-title":"Nucleic Acid Ther."},{"key":"2020110419231440600_B75","doi-asserted-by":"crossref","first-page":"7793","DOI":"10.1073\/pnas.1901947116","article-title":"Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development","volume":"116","author":"Vallabh","year":"2019","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2020110419231440600_B76","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1074\/mcp.RA119.001702","article-title":"Domain-specific quantification of prion protein in cerebrospinal fluid by targeted mass spectrometry","volume":"18","author":"Minikel","year":"2019","journal-title":"Mol. Cell Proteomics"},{"key":"2020110419231440600_B77","doi-asserted-by":"crossref","first-page":"e1008653","DOI":"10.1371\/journal.ppat.1008653","article-title":"Genome-wide transcriptomics identifies an early preclinical signature of prion infection","volume":"16","author":"Sorce","year":"2020","journal-title":"PLoS Pathog"},{"key":"2020110419231440600_B78","article-title":"Neurofilament light chain (NfL) as a possible biomarker for drug efficacy in mouse models of neurodegenerative diseases","author":"Hirouchi","year":"2019"},{"key":"2020110419231440600_B79","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1073\/pnas.0610779104","article-title":"The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases","volume":"104","author":"Steele","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B80","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/379339a0","article-title":"Normal host prion protein necessary for scrapie-induced neurotoxicity","volume":"379","author":"Brandner","year":"1996","journal-title":"Nature"},{"key":"2020110419231440600_B81","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.1038\/ncomms5347","article-title":"Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked","volume":"5","author":"Sandberg","year":"2014","journal-title":"Nat. Commun."},{"key":"2020110419231440600_B82","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1124\/jpet.113.212407","article-title":"Pharmacology of a central nervous system delivered 2\u2032-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates","volume":"350","author":"Rigo","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2020110419231440600_B83","doi-asserted-by":"crossref","first-page":"14508","DOI":"10.1073\/pnas.1006551107","article-title":"Analysis of proteome dynamics in the mouse brain","volume":"107","author":"Price","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2020110419231440600_B84","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1016\/j.ymthe.2017.06.002","article-title":"RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus","volume":"25","author":"Liang","year":"2017","journal-title":"Mol. Ther."},{"key":"2020110419231440600_B85","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.omtn.2017.04.005","article-title":"Evaluation of antisense oligonucleotides targeting ATXN3 in SCA3 mouse models","volume":"7","author":"Moore","year":"2017","journal-title":"Mol Ther Nucleic Acids"},{"key":"2020110419231440600_B86","doi-asserted-by":"crossref","first-page":"e131175","DOI":"10.1172\/jci.insight.131175","article-title":"Antisense oligonucleotides extend survival of prion-infected mice","volume":"5","author":"Raymond","year":"2019","journal-title":"JCI Insight"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/nar\/article-pdf\/48\/19\/10615\/34133459\/gkaa616.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/nar\/article-pdf\/48\/19\/10615\/34133459\/gkaa616.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T20:28:19Z","timestamp":1604521699000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/48\/19\/10615\/5878830"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,10]]},"references-count":86,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,8,10]]},"published-print":{"date-parts":[[2020,11,4]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkaa616","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.03.27.011940","asserted-by":"object"}]},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,11,4]]},"published":{"date-parts":[[2020,8,10]]}}}