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 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.
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All next-generation sequencing data generated in the present study are available from the BioProject database using accession PRJNA479953. All other datasets and materials are available from the corresponding authors upon reasonable request.
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This work was supported by the Medical Research Council (MC_U105697135 and MC_UU_00015/4 to M.M., MC_UU_12022/6 to C.F. and MC_UU_00015/5 to M.Z.), ERC Advanced Grant (FP7-322424 to M.Z.), NRJ-Institut de France (to M.Z.) and the Max Planck Society (to J.B.S.). P.R.-G. was supported by ‘Fundação para a Ciência e a Tecnologia’ (PD/BD/105750/2014). We acknowledge the important contribution to model development made by N.-G. Larsson, which was essential to this work. We are grateful to the personnel at Phenomics Animal Care Facility, Cambridge, UK, for their technical support in managing our mouse colonies. We are grateful to M. Rice, Phenomics Animal Care Facility, for technical assistance with viral administration. We thank R. Dirksen (MPI, Cologne, Germany) for isolation and immortalization of the MEFs. All FACS experiments were performed at the NIHR BRC Cell Phenotyping Hub, Cambridge, UK, by C. Bowman, E. Perez, J. Markovic Djuric and A. Petrunkina-Harrison.