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dc.contributor.authorBorel, Florie
dc.contributor.authorGernoux, Gwladys
dc.contributor.authorSun, Huaming
dc.contributor.authorStock, Rachel
dc.contributor.authorBlackwood, Meghan
dc.contributor.authorBrown, Robert H. Jr.
dc.contributor.authorMueller, Christian
dc.date2022-08-11T08:08:23.000
dc.date.accessioned2022-08-23T15:53:32Z
dc.date.available2022-08-23T15:53:32Z
dc.date.issued2018-10-31
dc.date.submitted2018-11-05
dc.identifier.citation<p>Sci Transl Med. 2018 Oct 31;10(465). pii: eaau6414. doi: 10.1126/scitranslmed.aau6414.</p>
dc.identifier.issn1946-6242
dc.identifier.doi10.1126/scitranslmed.aau6414
dc.identifier.pmid30381409
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29375
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by degeneration of motor neurons leading to rapidly progressive paralysis. About 10% of cases are caused by gain-of-function mutations that are transmitted as dominant traits. A potential therapy for these cases is to suppress the expression of the mutant gene. Here, we investigated silencing of SOD1, a gene commonly mutated in familial ALS, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA) that targeted SOD1 In a superoxide dismutase 1 (SOD1)-mediated mouse model of ALS, we have previously demonstrated that SOD1 silencing delayed disease onset, increased survival time, and reduced muscle loss and motor and respiratory impairments. Here, we describe the preclinical characterization of this approach in cynomolgus macaques (Macaca fascicularis) using an AAV serotype for delivery that has been shown to be safe in clinical trials. We optimized AAV delivery to the spinal cord by preimplantation of a catheter and placement of the subject with head down at 30° during intrathecal infusion. We compared different promoters for the expression of artificial miRNAs directed against mutant SOD1 Results demonstrated efficient delivery and effective silencing of the SOD1 gene in motor neurons. These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1-linked ALS.
dc.language.isoen_US
dc.relation<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/30381409" target="_blank">Link to article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1126/scitranslmed.aau6414
dc.subjectAmyotrophic lateral sclerosis
dc.subjectALS
dc.subjectgene silencing
dc.subjectSOD1
dc.subjectadeno-associated virus
dc.subjectAAV
dc.subjectmicroRNA
dc.subjectmiRNA
dc.subjectGenetics and Genomics
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.subjectTherapeutics
dc.subjectTranslational Medical Research
dc.titleSafe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques
dc.typeJournal Article
dc.source.journaltitleScience Translational Medicine
dc.source.volume10
dc.source.issue465
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1604
dc.identifier.contextkey13248894
html.description.abstract<p>Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by degeneration of motor neurons leading to rapidly progressive paralysis. About 10% of cases are caused by gain-of-function mutations that are transmitted as dominant traits. A potential therapy for these cases is to suppress the expression of the mutant gene. Here, we investigated silencing of <em>SOD1</em>, a gene commonly mutated in familial ALS, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA) that targeted <em>SOD1</em> In a superoxide dismutase 1 (SOD1)-mediated mouse model of ALS, we have previously demonstrated that <em>SOD1</em> silencing delayed disease onset, increased survival time, and reduced muscle loss and motor and respiratory impairments. Here, we describe the preclinical characterization of this approach in cynomolgus macaques (<em>Macaca fascicularis</em>) using an AAV serotype for delivery that has been shown to be safe in clinical trials. We optimized AAV delivery to the spinal cord by preimplantation of a catheter and placement of the subject with head down at 30° during intrathecal infusion. We compared different promoters for the expression of artificial miRNAs directed against mutant <em>SOD1</em> Results demonstrated efficient delivery and effective silencing of the <em>SOD1</em> gene in motor neurons. These results support the notion that gene therapy with an artificial miRNA targeting <em>SOD1</em> is safe and merits further development for the treatment of mutant <em>SOD1</em>-linked ALS.</p>
dc.identifier.submissionpathfaculty_pubs/1604
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentDepartment of Neurology
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pageseaau6414


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