Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.

TitleGenome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.
Publication TypeJournal Article
Year of Publication2018
AuthorsGammage, PA, Viscomi, C, Simard, M-L, Costa, ASH, Gaude, E, Powell, CA, Van Haute, L, McCann, BJ, Rebelo-Guiomar, P, Cerutti, R, Zhang, L, Rebar, EJ, Zeviani, M, Frezza, C, Stewart, JB, Minczuk, MA
JournalNat Med
Date Published2018 Nov

Mutations 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 tRNA 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.

Alternate JournalNat. Med.
Citation Key10.1038/s41591-018-0165-9
PubMed ID30250142
PubMed Central IDPMC6225988
Grant List322424 / / European Research Council / International
MC_U105697135 / / Medical Research Council / United Kingdom
MC_UU_00015/5 / / Medical Research Council / United Kingdom
MC_UU_12022/6 / / Medical Research Council / United Kingdom