{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:11:09Z","timestamp":1789776669523,"version":"4.0.1"},"posted":{"date-parts":[[2025,8,20]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Health USA","award":["UG3\/UH3NS115608"],"award-info":[{"award-number":["UG3\/UH3NS115608"]}]},{"name":"National Institute of Health USA","award":["R33NS115161"],"award-info":[{"award-number":["R33NS115161"]}]},{"name":"National Institute of Health USA","award":["R01NS095969"],"award-info":[{"award-number":["R01NS095969"]}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["AL230138"],"award-info":[{"award-number":["AL230138"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Kissick Family Foundation Frontotemporal Dementia Grant Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  TAR DNA-binding protein 43kDa (TDP-43) dysfunction is an early pathogenic mechanism that underlies amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that lacks disease modifying therapies. We previously developed a mouse model in which TDP-43 is selectively deleted from motor neurons (\n                  <jats:italic>\n                    ChAT-Cre;Tardbp\n                    <jats:sup>f\/f<\/jats:sup>\n                  <\/jats:italic>\n                  ) that mimics the early stages of ALS. Here, we demonstrate that intravenous delivery of a blood-brain-barrier (BBB) permeable AAV capsid expressing our rationally designed splicing repressor CTR (AAV-PHP.eB-CTR) in symptomatic\n                  <jats:italic>\n                    ChAT-Cre;Tardbp\n                    <jats:sup>f\/f<\/jats:sup>\n                  <\/jats:italic>\n                  mice markedly slowed disease progression and prevented paralysis. Systemic delivery of AAV-PHP.eB-CTR led to transduction of \u223c80% of spinal motor neurons, repression of TDP-43-associated cryptic exons within motor neurons expressing CTR, and attenuation of motor neuron loss. Notably, the addition of the\n                  <jats:italic>TARDBP<\/jats:italic>\n                  3\u2019UTR autoregulatory element to CTR maintained its expression within a physiological range. In control littermates that received AAV-PHP.eB-CTR and were monitored for &gt;20 months, grip strength and body weight remained normal, and no histopathological abnormalities were observed, underscoring a favorable safety profile for this gene therapy. These results provide preclinical proof-of-concept that BBB-crossing AAV delivery of CTR can rescue motor neuron disease through the restoration of TDP-43 function, offering a promising mechanism-based therapeutic strategy for ALS.\n                <\/jats:p>","DOI":"10.1101\/2025.08.14.670400","type":"posted-content","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T19:35:13Z","timestamp":1755718513000},"source":"Crossref","is-referenced-by-count":5,"title":["Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-5156","authenticated-orcid":false,"given":"Aswathy","family":"Peethambaran Mallika","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8806-5356","authenticated-orcid":false,"given":"Jessica G.","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Opal","family":"Sitzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3988-6438","authenticated-orcid":false,"given":"Meghraj Singh","family":"Baghel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6079-1138","authenticated-orcid":false,"given":"Shruti","family":"Renganathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7019","authenticated-orcid":false,"given":"Irika R.","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Melnikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-9729","authenticated-orcid":false,"given":"Jonathan P.","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-3274","authenticated-orcid":false,"given":"Philip 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