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Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges

Abstract

The variable clinical and biochemical manifestations of primary mitochondrial diseases (PMDs), and the complexity of mitochondrial genetics, have proven to be a substantial barrier to the development of effective disease-modifying therapies. Encouraging data from gene therapy trials in patients with Leber hereditary optic neuropathy and advances in DNA editing techniques have raised expectations that successful clinical transition of genetic therapies for PMDs is feasible. However, obstacles to the clinical application of genetic therapies in PMDs remain; the development of innovative, safe and effective genome editing technologies and vectors will be crucial to their future success and clinical approval. In this Perspective, we review progress towards the genetic treatment of nuclear and mitochondrial DNA-related PMDs. We discuss advances in mitochondrial DNA editing technologies alongside the unique challenges to targeting mitochondrial genomes. Last, we consider ongoing trials and regulatory requirements.

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Fig. 1: A potential strategy for correction of loss-of-function primary mitochondrial disease variants.
Fig. 2: Potential strategies for the correction of dominant primary mitochondrial disease phenotypes.
Fig. 3: Timeline of research into genetic treatments for primary mitochondria diseases.

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Acknowledgements

C.V. is supported by the Telethon Foundation (GGP20013), AFM-Telethon (23706), Associazione Luigi Comini Onlus, Department of Biomedical Sciences-UNIPD (SID2022- VISC_BIRD2222_01). M.M. is supported by the Medical Research Council (MC_UU_00028/3). R.D.S.P. and M.F. are supported by a Medical Research Council (UK) Clinician Scientist Fellowship (MR/S002065/1). M.F., M.M., M.G.H, C.V., and R.D.S.P. are supported by Medical Research Council (UK) award MC_PC_21046 to establish a National Mouse Genetics Network Cluster in Mitochondria (MitoCluster). M.G.H. and R.D.S.P. are supported by Medical Research Council (UK) strategic award MR/S005021/1 to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD).

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Correspondence to Robert D. S. Pitceathly.

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M.M. is a co-founder, shareholder, and member of the Scientific Advisory Board of Pretzel Therapeutics. The other authors declare no competing interests.

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Nature Reviews Neurology thanks Robert Lightowlers, Ramon Martí, Yuma Yamada and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Cybrid

A cytoplasmic hybrid created by fusing cells harbouring a wild-type or altered mtDNA of interest with cells depleted of endogenous mtDNA.

Heteroplasmy shift

A shift in the relative abundance of mutant mtDNA to wild-type mtDNA.

Indels

The insertion and/or deletion of one or more nucleotides in a DNA sequence.

Restriction sites

A short sequence of DNA that can be recognized and cleaved by restriction enzymes.

Stoichiometry

The quantitative relationship between two or more substances forming a compound.

Tropism

The ability of different viral strains to infect specific cell types or tissues.

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Falabella, M., Minczuk, M., Hanna, M.G. et al. Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges. Nat Rev Neurol 18, 689–698 (2022). https://doi.org/10.1038/s41582-022-00715-9

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