In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.

Authors
Silva-Pinheiro, Pedro  ORCID logo  https://orcid.org/0000-0002-0872-5749
Nash, Pavel A 

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Article
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Abstract

Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.

Publication Date
2022-02-08
Online Publication Date
2022-02-08
Acceptance Date
2022-01-21
Keywords
Animals, DNA, Mitochondrial, Dependovirus, Female, Gene Editing, Genes, Mitochondrial, Genetic Therapy, Genetic Vectors, Humans, Male, Mice, Mitochondria, Mitochondrial Diseases, Models, Animal, Mutagenesis, Mutation, Proof of Concept Study
Journal Title
Nat Commun
Journal ISSN
2041-1723
2041-1723
Volume Title
13
Publisher
Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_00015/4)