Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo

Gammage, P. A. et al. (2018) Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nature Medicine, 24(11), pp. 1691-1695. (doi: 10.1038/s41591-018-0165-9) (PMID:30250142) (PMCID:PMC6225988)

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227928.pdf - Accepted Version



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.

Item Type:Articles
Additional Information: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.
Glasgow Author(s) Enlighten ID:Gammage, Dr Payam
Authors: Gammage, P. A., Viscomi, C., Simard, M.-L., Costa, A. S. H., Gaude, E., Powell, C. A., Van Haute, L., McCann, B. J., Rebelo-Guiomar, P., Cerutti, R., Zhang, L., Rebar, E. J., Zeviani, M., Frezza, C., Stewart, J. B., and Minczuk, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Medicine
Publisher:Nature Research
ISSN (Online):1546-170X
Published Online:24 September 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Nature Medicine 24(11): 1691-1695
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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