{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:06:18Z","timestamp":1791396378515,"version":"4.3.3"},"posted":{"date-parts":[[2025,11,30]]},"group-title":"Neuroscience","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["DRI-TAP2021-11"],"award-info":[{"award-number":["DRI-TAP2021-11"]}],"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DRI-LTA2023\/4"],"award-info":[{"award-number":["DRI-LTA2023\/4"]}],"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DRI-1203"],"award-info":[{"award-number":["DRI-1203"]}],"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DRI-6204"],"award-info":[{"award-number":["DRI-6204"]}],"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["102186\/B\/13\/Z"],"award-info":[{"award-number":["102186\/B\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["215508\/Z\/19\/Z"],"award-info":[{"award-number":["215508\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"crossref","award":["893-791"],"award-info":[{"award-number":["893-791"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"crossref","award":["2457-797"],"award-info":[{"award-number":["2457-797"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["AARF-1308004"],"award-info":[{"award-number":["AARF-1308004"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54NS123743"],"award-info":[{"award-number":["U54NS123743"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MR\/Z505353\/1"],"award-info":[{"award-number":["MR\/Z505353\/1"]}]},{"name":"Medical Research Council","award":["MR\/M008606\/1"],"award-info":[{"award-number":["MR\/M008606\/1"]}]},{"name":"Medical Research Council","award":["MR\/S006508\/1"],"award-info":[{"award-number":["MR\/S006508\/1"]}]},{"name":"Live Like Lou Foundation"},{"id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including\n                  <jats:italic>UNC13A<\/jats:italic>\n                  and\n                  <jats:italic>STMN2<\/jats:italic>\n                  , disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement\n                  <jats:italic>in vivo<\/jats:italic>\n                  , positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.\n                <\/jats:p>","DOI":"10.1101\/2025.11.26.690143","type":"posted-content","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T20:35:21Z","timestamp":1764534921000},"source":"Crossref","is-referenced-by-count":3,"title":["U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-407X","authenticated-orcid":false,"given":"Puja R.","family":"Mehta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-6948","authenticated-orcid":false,"given":"Tomas","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-4586","authenticated-orcid":false,"given":"Sarah","family":"Pickles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-0227","authenticated-orcid":false,"given":"Peter","family":"Harley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8360-2536","authenticated-orcid":false,"given":"Michela","family":"Barioglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4505-9068","authenticated-orcid":false,"given":"Christoph","family":"Schweingruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8470-4085","authenticated-orcid":false,"given":"Alessandro","family":"Marrero-Gagliardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4542-7062","authenticated-orcid":false,"given":"Yujing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0306-5796","authenticated-orcid":false,"given":"Francesca","family":"Mattedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8380-2931","authenticated-orcid":false,"given":"Simone","family":"Barattucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2769-8763","authenticated-orcid":false,"given":"Lilian Tsai-Wei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9921-1755","authenticated-orcid":false,"given":"Eugeni","family":"Ryadnov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3343-1547","authenticated-orcid":false,"given":"Matteo","family":"Zanovello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9624-9067","authenticated-orcid":false,"given":"Alexander J.","family":"Cammack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6820-5534","authenticated-orcid":false,"given":"Adrian M.","family":"Isaacs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1233-668X","authenticated-orcid":false,"given":"Juan","family":"Burrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-0146","authenticated-orcid":false,"given":"Christopher E.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2628-4115","authenticated-orcid":false,"given":"Matthew J.","family":"Keuss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-129X","authenticated-orcid":false,"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8762-8188","authenticated-orcid":false,"given":"Pietro","family":"Fratta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-9800","authenticated-orcid":false,"given":"Marc-David","family":"Ruepp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120200302412000_2025.11.26.690143v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"2025120200302412000_2025.11.26.690143v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab0983"},{"key":"2025120200302412000_2025.11.26.690143v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04436-3"},{"key":"2025120200302412000_2025.11.26.690143v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04424-7"},{"key":"2025120200302412000_2025.11.26.690143v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00608-5"},{"key":"2025120200302412000_2025.11.26.690143v1.6","doi-asserted-by":"crossref","unstructured":"Keuss, M.J. , et al. Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A spliceswitching ASOs. bioRxiv (2024).","DOI":"10.1101\/2024.06.20.599684"},{"key":"2025120200302412000_2025.11.26.690143v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0300-4"},{"key":"2025120200302412000_2025.11.26.690143v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0293-z"},{"key":"2025120200302412000_2025.11.26.690143v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111001"},{"key":"2025120200302412000_2025.11.26.690143v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq5622"},{"key":"2025120200302412000_2025.11.26.690143v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-004-4190-0"},{"key":"2025120200302412000_2025.11.26.690143v1.12","unstructured":"Waldrop, M. , Nationwide Children\u2019s, Hospital. Phase I\/IIa Systemic Gene Delivery Clinical Trial of scAAV9.U7.ACCA for Exon 2 Duplication-Associated Duchenne Muscular Dystrophy. (2020)."},{"key":"2025120200302412000_2025.11.26.690143v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.113"},{"key":"2025120200302412000_2025.11.26.690143v1.14","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1038\/mt.2016.152","article-title":"Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing","volume":"24","year":"2016","journal-title":"Mol Ther"},{"key":"2025120200302412000_2025.11.26.690143v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2779"},{"key":"2025120200302412000_2025.11.26.690143v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211577110"},{"key":"2025120200302412000_2025.11.26.690143v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00846-7"},{"key":"2025120200302412000_2025.11.26.690143v1.18","doi-asserted-by":"crossref","first-page":"101144","DOI":"10.1016\/j.omtm.2023.101144","article-title":"Persistence of exon 2 skipping and dystrophin expression at 18 months after U7snRNA-mediated therapy in the Dup2 mouse model","volume":"31","year":"2023","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2025120200302412000_2025.11.26.690143v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2778"},{"key":"2025120200302412000_2025.11.26.690143v1.20","doi-asserted-by":"publisher","DOI":"10.1002\/cpsc.45"},{"key":"2025120200302412000_2025.11.26.690143v1.21","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"2025120200302412000_2025.11.26.690143v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2840"},{"key":"2025120200302412000_2025.11.26.690143v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.51"},{"key":"2025120200302412000_2025.11.26.690143v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.014"},{"key":"2025120200302412000_2025.11.26.690143v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4490"},{"key":"2025120200302412000_2025.11.26.690143v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa9344"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.26.690143","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:06:42Z","timestamp":1768471602000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.26.690143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,30]]},"references-count":26,"URL":"https:\/\/doi.org\/10.1101\/2025.11.26.690143","relation":{},"subject":[],"published":{"date-parts":[[2025,11,30]]},"subtype":"preprint"}}