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dc.contributor.authorKumar, Meenakshi Sundaram
dc.contributor.authorFowler-Magaw, Megan E
dc.contributor.authorKulick, Daniel
dc.contributor.authorBoopathy, Sivakumar
dc.contributor.authorGadd, Del Hayden
dc.contributor.authorRotunno, Melissa
dc.contributor.authorDouthwright, Catherine
dc.contributor.authorGolebiowski, Diane
dc.contributor.authorYusuf, Issa
dc.contributor.authorXu, Zuoshang
dc.contributor.authorBrown, Robert H
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorO'Neil, Alison L
dc.contributor.authorBosco, Daryl A
dc.date.accessioned2023-03-02T19:48:21Z
dc.date.available2023-03-02T19:48:21Z
dc.date.issued2022-12-16
dc.identifier.citationKumar MS, Fowler-Magaw ME, Kulick D, Boopathy S, Gadd DH, Rotunno M, Douthwright C, Golebiowski D, Yusuf I, Xu Z, Brown RH Jr, Sena-Esteves M, O'Neil AL, Bosco DA. Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons. Int J Mol Sci. 2022 Dec 16;23(24):16013. doi: 10.3390/ijms232416013. PMID: 36555655; PMCID: PMC9784173.en_US
dc.identifier.eissn1422-0067
dc.identifier.doi10.3390/ijms232416013en_US
dc.identifier.pmid36555655
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51735
dc.description.abstractALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.en_US
dc.description.sponsorshipThis project was also funded by the Angel Fund for ALS Research for R.H.B.J.; the Pilot Project Program grant UL1TR001453 from the UMass Center for Clinical and Translational Science (UMCCTS) for D.A.B., M.E.-S., and R.H.B.J.; and NIH/NINDS R01 NS067206 for D.A.B.
dc.language.isoenen_US
dc.relation.ispartofInternational Journal of Molecular Sciencesen_US
dc.relation.urlhttps://doi.org/10.3390/ijms232416013en_US
dc.rightsCopyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectamyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)en_US
dc.subjectantibody engineeringen_US
dc.subjectneurite outgrowthen_US
dc.subjectprotein misfoldingen_US
dc.subjectsuperoxide dismutase (SOD)en_US
dc.subjectUMCCTS funding
dc.titleAnti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neuronsen_US
dc.typeJournal Articleen_US
dc.source.journaltitleInternational journal of molecular sciences
dc.source.volume23
dc.source.issue24
dc.source.countrySwitzerland
dc.identifier.journalInternational journal of molecular sciences
refterms.dateFOA2023-03-02T19:48:21Z
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurologyen_US
dc.description.thesisprogramBiochemistry and Molecular Biotechnology
dc.description.thesisprogramNeuroscience


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Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Except where otherwise noted, this item's license is described as Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).