In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.

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cam.issuedOnline2022-02-08
dc.contributor.authorSilva-Pinheiro, Pedro
dc.contributor.authorNash, Pavel A
dc.contributor.authorVan Haute, Lindsey
dc.contributor.authorMutti, Christian D
dc.contributor.authorTurner, Keira
dc.contributor.authorMinczuk, Michal
dc.contributor.orcidSilva-Pinheiro, Pedro [0000-0002-0872-5749]
dc.contributor.orcidVan Haute, Lindsey [0000-0001-7809-1473]
dc.contributor.orcidMutti, Christian D [0000-0001-5091-5055]
dc.contributor.orcidTurner, Keira [0000-0001-9586-9523]
dc.contributor.orcidMinczuk, Michal [0000-0001-8242-1420]
dc.date.accessioned2022-03-14T02:04:08Z
dc.date.available2022-03-14T02:04:08Z
dc.date.issued2022-02-08
dc.date.updated2022-03-14T02:04:07Z
dc.description.abstractMitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.
dc.identifier.doi10.17863/CAM.82379
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.otherPMC8825850
dc.identifier.other35136065
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334941
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-022-28358-w
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101528555
dc.sourceessn: 2041-1723
dc.subjectAnimals
dc.subjectDNA, Mitochondrial
dc.subjectDependovirus
dc.subjectFemale
dc.subjectGene Editing
dc.subjectGenes, Mitochondrial
dc.subjectGenetic Therapy
dc.subjectGenetic Vectors
dc.subjectHumans
dc.subjectMale
dc.subjectMice
dc.subjectMitochondria
dc.subjectMitochondrial Diseases
dc.subjectModels, Animal
dc.subjectMutagenesis
dc.subjectMutation
dc.subjectProof of Concept Study
dc.titleIn vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
dc.typeArticle
dcterms.dateAccepted2022-01-21
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
pubs.funder-project-idMedical Research Council (MC_UU_00015/4)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-022-28358-w
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