Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer

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dc.contributor.authorBustos, Fernando J.
dc.contributor.authorPandian, Swarna
dc.contributor.authorHaensgen, Henny
dc.contributor.authorZhao, Jian-Ping
dc.contributor.authorStrouf, Haley
dc.contributor.authorHeidenreich, Matthias
dc.contributor.authorSwiech, Lukasz
dc.contributor.authorDeverman, Benjamin E.
dc.contributor.authorGradinaru, Viviana
dc.contributor.authorZhang, Feng
dc.contributor.authorConstantine-Paton, Martha
dc.date.accessioned2024-03-26T12:59:16Z
dc.date.available2024-03-26T12:59:16Z
dc.date.issued2023-12
dc.descriptionIndexación: Scopus.
dc.description.abstractBackground: Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Results: Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD. Conclusions: Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases. © 2023, BioMed Central Ltd., part of Springer Nature.
dc.description.urihttps://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01714-y
dc.identifier.citationBMC Biology. Volume 21, Issue 1. December 2023. Article number 232
dc.identifier.doi10.1186/s12915-023-01714-y
dc.identifier.issn1741-7007
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/55316
dc.language.isoen
dc.publisherBioMed Central Ltd
dc.rights.licenseCC BY 4.0 DEED Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnxiety
dc.subjectASD
dc.subjectDN-CRISPR
dc.subjectGene-editing
dc.subjectTherapy
dc.titleRemoval of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer
dc.typeArtículo
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