Development of a targeted BioPROTAC degrader selective for misfolded SOD1

Development of a targeted BioPROTAC degrader selective for misfolded SOD1 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Development of a targeted BioPROTAC degrader selective for misfolded SOD1 Jeremy Lum, Christen Chisholm, Rachael Bartlett, Mikayla Brown, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6070925/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The accumulation of misfolded protein species underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein; SOD1, using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction revealed a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cultured cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1G93A mouse model of ALS. Delayed disease progression was associated with protection of motor neurons, reduced accumulation of insoluble SOD1 and protection of neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases. Health sciences/Medical research/Drug development Health sciences/Medical research/Preclinical research Full Text Additional Declarations Yes there is potential Competing Interest. N.R.C, C.C and J.J.Y are the owners of an international patent (PCT/CA2024/050200) titled “Antibodies and Ubiquitin Ligase Fusion Proteins for Misfolded Superoxide Dismutase-1 (SOD-1)”. The sequences of misfolded SOD1 antibodies used in this manuscript is owned by the University of British Columbia and licensed by ProMIS Neurosciences. N. R. C. is the Chief Scientific Officer of ProMIS Neurosciences. N. R. C. have received consultation compensation from ProMIS and possess ProMIS stock and stock options. All other authors declare that they have no conflicts of interest with the contents of this article. Supplementary Files Chisholmetal.nrcompetinginterests.pdf nr-competing-interests Chisholmetal.nrreportingsummaryflat.pdf nr-reporting-summary Chisholmetal.Supplementaryfiguresandtables.pdf Supplementary figures and tables Chisholmetal.SupplementaryT2.xlsx Supplementary Table 2 Chisholmetal.SupplementaryVideo1.mov Supplementary Video 1 Chisholmetal.SupplementaryVideo2.mov Supplementary Video 2 Chisholmetal.SourceData.xlsx Source data Cite Share Download PDF Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6070925","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":423932898,"identity":"8ea33ac1-e77e-45f4-b848-67ecd7f4d668","order_by":0,"name":"Jeremy 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