{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:49:47Z","timestamp":1787010587390,"version":"build-2736575974"},"posted":{"date-parts":[[2024,12,9]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["IGNITE R61\/R33 NS119717"],"award-info":[{"award-number":["IGNITE R61\/R33 NS119717"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["URGenT U01 NS132994"],"award-info":[{"award-number":["URGenT U01 NS132994"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Prion protein (PrP) lowering is effective in animal models of prion disease and is being tested clinically in prion disease patients, but there remains a need for more potent PrP-lowering drug candidates. Inspired by the reported potency and duration of action of divalent short interfering RNA (siRNA), a new oligonucleotide drug modality for the central nervous system, we sought to discover and develop a new PrP-lowering drug candidate. Herein we identify a mouse\n                  <jats:italic>Prnp<\/jats:italic>\n                  -targeting divalent siRNA molecule, 1682-s4, that lowers PrP to 49% residual brain expression in wild-type mice, and, in the context of intracerebral infection with Rocky Mountain Laboratory (RML) prions, achieves a 2.7-fold increase in survival time with pre-symptomatic chronic treatment and 64% increase in survival time with a single dose after symptom onset. We describe the generation of two transgenic mouse lines, Tg25109 and Tg26372, expressing the full human\n                  <jats:italic>PRNP<\/jats:italic>\n                  gene and its non-coding sequence, and demonstrate their utility for in vivo discovery of potent human\n                  <jats:italic>PRNP<\/jats:italic>\n                  -targeting oligonucleotides. We discover siRNA sequence 2439 against human\n                  <jats:italic>PRNP<\/jats:italic>\n                  and compare its potency in different divalent siRNA chemical scaffolds. We determine that both the fixed UU tail and extended nucleic acid linkages of scaffold s4 contribute to superior potency compared to other scaffolds tested, offering 9.4 and 15.9 percentage points respectively of additional PrP knockdown. A single dose of 348 \u00b5g of 2439-s4 lowered whole brain hemisphere human PrP in transgenic mice to 17% residual after 30 days, while 52 \u00b5g lowered PrP to 49% residual. 1-2% of the dose of 2439-s4 delivered into cerebrospinal fluid is retained in the brain, and the median effective tissue concentration is estimated at 1.2 micrograms per gram of tissue. Good Laboratory Practices toxicology studies identified no significant liabilities, and the U.S. FDA has cleared an Investigational New Drug application to bring 2439-s4 into clinical trials.\n                <\/jats:p>","DOI":"10.1101\/2024.12.05.627039","type":"posted-content","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T18:00:12Z","timestamp":1733767212000},"source":"Crossref","is-referenced-by-count":18,"title":["Divalent siRNA for prion disease"],"prefix":"10.64898","author":[{"given":"Juliana E","family":"Gentile","sequence":"first","affiliation":[{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4167-8291","authenticated-orcid":false,"given":"Taylor L","family":"Corridon","sequence":"additional","affiliation":[{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7377-219X","authenticated-orcid":false,"given":"Fiona E","family":"Serack","sequence":"additional","affiliation":[{"name":"Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimas","family":"Echeverria","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, UMass Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary C","family":"Kennedy","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, UMass Chan Medical School, Worcester, MA, 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrie L","family":"Gallant-Behm","sequence":"additional","affiliation":[{"name":"Atalanta Therapeutics, Boston, MA, 02210, 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