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dc.contributor.authorBorel, Florie
dc.contributor.authorGernoux, Gwladys
dc.contributor.authorCardozo, Brynn
dc.contributor.authorMetterville, Jake P.
dc.contributor.authorToro Cabrera, Gabriela
dc.contributor.authorSong, Lina
dc.contributor.authorSu, Qin
dc.contributor.authorGao, Guang Ping
dc.contributor.authorElmallah, Mai K.
dc.contributor.authorBrown, Robert H. Jr.
dc.contributor.authorMueller, Christian
dc.date2022-08-11T08:09:44.000
dc.date.accessioned2022-08-23T16:41:49Z
dc.date.available2022-08-23T16:41:49Z
dc.date.issued2016-01-01
dc.date.submitted2016-05-18
dc.identifier.citation<p>Hum Gene Ther. 2016 Jan;27(1):19-31. doi: 10.1089/hum.2015.122. <a href="http://dx.doi.org/10.1089/hum.2015.122">Link to article on publisher's site</a></p>
dc.identifier.issn1043-0342 (Linking)
dc.identifier.doi10.1089/hum.2015.122
dc.identifier.pmid26710998
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39962
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26710998&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © Florie Borel, et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectGenetics and Genomics
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNervous System Diseases
dc.subjectTherapeutics
dc.titleTherapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates
dc.typeJournal Article
dc.source.journaltitleHuman gene therapy
dc.source.volume27
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3776&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2771
dc.identifier.contextkey8614725
refterms.dateFOA2022-08-23T16:41:49Z
html.description.abstract<p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.</p>
dc.identifier.submissionpathoapubs/2771
dc.contributor.departmentDepartment of Pediatrics, Division of Pediatric Pulmonology
dc.contributor.departmentVector Core
dc.contributor.departmentDepartment of Neurology
dc.contributor.departmentGene Therapy Center
dc.source.pages19-31


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Copyright © Florie Borel, et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Except where otherwise noted, this item's license is described as Copyright © Florie Borel, et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.