{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:52:35Z","timestamp":1785433955687,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,27]]},"group-title":"Biochemistry","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM147498"],"award-info":[{"award-number":["R35GM147498"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM153249"],"award-info":[{"award-number":["R35GM153249"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM145289"],"award-info":[{"award-number":["R35GM145289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21NS142950"],"award-info":[{"award-number":["R21NS142950"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Creutzfeldt-Jakob Disease (CJD) Foundation"},{"id":[{"id":"https:\/\/ror.org\/000dswa46","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/0492gsr48","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/014nxkk19","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Prion diseases are fatal neurodegenerative disorders driven by prion protein (PrP) misfolding, and lowering cellular PrP represents a promising therapeutic strategy. Here we report a small-molecule approach that reduces PrP by modulating pre-mRNA splicing of the\n                  <jats:italic>PRNP<\/jats:italic>\n                  gene. Through chemical modification of the clinically approved splicing modulator risdiplam, we generated CP3, the first class of compounds that selectively activate a cryptic exon in\n                  <jats:italic>PRNP<\/jats:italic>\n                  and routes its mRNA product for degradation, reducing PrP by \u223c70% in cells. We demonstrate that CP3 activity critically depends on alternative splicing factor Luc7L, revealing a novel requirement for alternative splicing factors in small molecule splicing modulation. Strikingly, co-administration of CP3 with a Luc7L activator PTC258 significantly lowers PrP levels in the brains of transgenic mice. These results establish splicing modulation as a powerful strategy for PrP reduction and highlight the potential of small-molecule cooperativity for therapeutic RNA targeting.\n                <\/jats:p>","DOI":"10.64898\/2026.06.26.734742","type":"posted-content","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T10:30:56Z","timestamp":1782642656000},"source":"Crossref","is-referenced-by-count":0,"title":["Depleting prion protein using splice-switching small molecules"],"prefix":"10.64898","author":[{"given":"Bo","family":"Liu","sequence":"first","affiliation":[{"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Fair","sequence":"additional","affiliation":[{"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, 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