Journal
NATURE MEDICINE
Volume 24, Issue 11, Pages 1691-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0165-9
Keywords
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Funding
- Medical Research Council [MC_U105697135, MC_UU_00015/4, MC_UU_12022/6, MC_UU_00015/5]
- ERC Advanced Grant [FP7-322424]
- NRJ-Institut de France
- Max Planck Society
- Fundacao para a Ciencia e a Tecnologia [PD/BD/105750/2014]
- MRC [MC_U105697135, MC_UU_00015/8, MC_UU_00015/4, MC_UU_00015/5, MC_UU_12022/6] Funding Source: UKRI
- Medical Research Council [MC_UU_00015/4] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [PD/BD/105750/2014] Funding Source: FCT
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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(Ala) 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.
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