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dc.contributor.authorGammage, Payam A
dc.contributor.authorViscomi, Carlo
dc.contributor.authorSimard, Marie-Lune
dc.contributor.authorCosta, Ana SH
dc.contributor.authorGaude, Edoardo
dc.contributor.authorPowell, Christopher A
dc.contributor.authorVan Haute, Lindsey
dc.contributor.authorMcCann, Beverly J
dc.contributor.authorRebelo-Guiomar, Pedro
dc.contributor.authorCerutti, Raffaele
dc.contributor.authorZhang, Lei
dc.contributor.authorRebar, Edward J
dc.contributor.authorZeviani, Massimo
dc.contributor.authorFrezza, Christian
dc.contributor.authorStewart, James B
dc.contributor.authorMinczuk, Michal
dc.date.accessioned2018-11-05T10:26:20Z
dc.date.available2018-11-05T10:26:20Z
dc.date.issued2018-11
dc.identifier.issn1078-8956
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284619
dc.description.abstractMutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectMitochondria, Heart
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDependovirus
dc.subjectMitochondrial Diseases
dc.subjectDisease Models, Animal
dc.subjectDNA, Mitochondrial
dc.subjectRNA, Transfer
dc.subjectPrognosis
dc.subjectMutation
dc.subjectGene Editing
dc.subjectZinc Finger Nucleases
dc.titleGenome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.
dc.typeArticle
prism.endingPage1695
prism.issueIdentifier11
prism.publicationDate2018
prism.publicationNameNat Med
prism.startingPage1691
prism.volume24
dc.identifier.doi10.17863/CAM.31993
dcterms.dateAccepted2018-07-26
rioxxterms.versionofrecord10.1038/s41591-018-0165-9
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidGammage, Payam A [0000-0003-1968-1726]
dc.contributor.orcidViscomi, Carlo [0000-0001-6050-0566]
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.contributor.orcidStewart, James B [0000-0002-2902-4968]
dc.contributor.orcidMinczuk, Michal [0000-0001-8242-1420]
dc.identifier.eissn1546-170X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_U105697135)
pubs.funder-project-idMedical Research Council (MC_UU_00015/4)
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idMedical Research Council (MC_UP_1002/1)
pubs.funder-project-idMRC (MC_UP_1002/1)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idEuropean Research Council (322424)
pubs.funder-project-idMedical Research Council (MC_UU_00015/8)
pubs.funder-project-idMRC (MC_UU_00015/8)
cam.issuedOnline2018-09-24
rioxxterms.freetoread.startdate2019-03-24


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