{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:20:32Z","timestamp":1766121632681,"version":"3.48.0"},"reference-count":37,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013013","name":"Target ALS Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013013","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012312","name":"Robert Packard Center for ALS Research at Johns Hopkins","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012312","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Alzheimer\u2019s Disease Strategic Fund grant","award":["ADSF-24-1284327-C"],"award-info":[{"award-number":["ADSF-24-1284327-C"]}]},{"name":"The Cure Alzheimer\u2019s Fund"},{"name":"Association for Frontotemporal Degeneration Biomarkers Initiative"},{"name":"Florida Department of Health Ed and Ethel Moore Alzheimer\u2019s Disease Research Program"},{"DOI":"10.13039\/100006312","name":"the BrightFocus Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Kissick Family Foundation"},{"name":"National Institutes of Health\/National Institute on Aging","award":["5P30AG0062677"],"award-info":[{"award-number":["5P30AG0062677"]}]},{"name":"National Institutes of Health\/National Institute on Aging","award":["ALLFTD U19AG063911"],"award-info":[{"award-number":["ALLFTD U19AG063911"]}]},{"name":"National Institutes of Health\/National Institute on Aging","award":["R01AG089380"],"award-info":[{"award-number":["R01AG089380"]}]},{"name":"National Institutes of Health\/National Institute on Aging","award":["R01AG085307"],"award-info":[{"award-number":["R01AG085307"]}]},{"name":"National Institutes of Health\/National Institute of Neurological Disorders and Stroke","award":["U54NS123743"],"award-info":[{"award-number":["U54NS123743"]}]},{"name":"National Institutes of Health\/National Institute of Neurological Disorders and Stroke","award":["R35 NS137447"],"award-info":[{"award-number":["R35 NS137447"]}]},{"name":"National Institutes of Health\/National Institute of Neurological Disorders and Stroke","award":["P01NS084974"],"award-info":[{"award-number":["P01NS084974"]}]},{"name":"National Institutes of Health\/National Institute of Neurological Disorders and Stroke","award":["R01NS132330"],"award-info":[{"award-number":["R01NS132330"]}]},{"name":"National Institutes of Health\/National Institute of Neurological Disorders and Stroke","award":["R01NS117461"],"award-info":[{"award-number":["R01NS117461"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS\/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS\/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS\/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS\/FTD.<\/jats:p>","DOI":"10.3390\/cells14242012","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T10:41:23Z","timestamp":1765968083000},"page":"2012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS\/FTD"],"prefix":"10.3390","volume":"14","author":[{"given":"Jingfen","family":"Su","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Alaiz Noya","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8976-4382","authenticated-orcid":false,"given":"Anuradha F.","family":"Lingappa","sequence":"additional","affiliation":[{"name":"Prosetta Biosciences, Inc., San Francisco, CA 94107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"Solas","sequence":"additional","affiliation":[{"name":"Prosetta Biosciences, Inc., San Francisco, CA 94107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimei","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lillian","family":"Daughrity","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Castanedes-Casey","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishe","family":"Kurti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishwanath R.","family":"Lingappa","sequence":"additional","affiliation":[{"name":"Prosetta Biosciences, Inc., San Francisco, CA 94107, USA"},{"name":"Department of Physiology, University of California, San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9900-4313","authenticated-orcid":false,"given":"Yongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00461-4","article-title":"Frontotemporal dementia","volume":"386","author":"Bang","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0140-6736(16)00737-6","article-title":"The frontotemporal dementia-motor neuron disease continuum","volume":"388","author":"Burrell","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s12031-011-9538-y","article-title":"Estimating the number of persons with frontotemporal lobar degeneration in the US population","volume":"45","author":"Knopman","year":"2011","journal-title":"J. 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