cam.issuedOnline	2022-02-08
dc.contributor.author	Silva-Pinheiro, Pedro
dc.contributor.author	Nash, Pavel A
dc.contributor.author	Van Haute, Lindsey
dc.contributor.author	Mutti, Christian D
dc.contributor.author	Turner, Keira
dc.contributor.author	Minczuk, Michal
dc.contributor.orcid	Silva-Pinheiro, Pedro [0000-0002-0872-5749]
dc.contributor.orcid	Van Haute, Lindsey [0000-0001-7809-1473]
dc.contributor.orcid	Mutti, Christian D [0000-0001-5091-5055]
dc.contributor.orcid	Turner, Keira [0000-0001-9586-9523]
dc.contributor.orcid	Minczuk, Michal [0000-0001-8242-1420]
dc.date.accessioned	2022-02-09T13:22:14Z
dc.date.available	2022-02-09T13:22:14Z
dc.date.issued	2022-02-08
dc.date.submitted	2021-09-14
dc.date.updated	2022-02-09T13:22:13Z
dc.description.abstract	Mitochondria 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.doi	10.17863/CAM.81201
dc.identifier.eissn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.other	s41467-022-28358-w
dc.identifier.other	28358
dc.identifier.uri	https://www.repository.cam.ac.uk/handle/1810/333784
dc.language	en
dc.publisher	Springer Science and Business Media LLC
dc.subject	Article
dc.subject	/631/80/642/333
dc.subject	/631/208/726/2129
dc.subject	/631/208/726
dc.subject	/45
dc.subject	/45/23
dc.subject	/45/70
dc.subject	/42
dc.subject	/42/44
dc.subject	article
dc.title	In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
dc.type	Article
dcterms.dateAccepted	2022-01-21
prism.issueIdentifier	1
prism.publicationName	Nat Commun
prism.volume	13
pubs.funder-project-id	Medical Research Council (MC_UU_00015/4)
rioxxterms.licenseref.uri	http://creativecommons.org/licenses/by/4.0/
rioxxterms.version	VoR
rioxxterms.versionofrecord	10.1038/s41467-022-28358-w

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

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