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

Author

Listed:
  • Pedro Silva-Pinheiro

    (University of Cambridge)

  • Pavel A. Nash

    (University of Cambridge)

  • Lindsey Van Haute

    (University of Cambridge)

  • Christian D. Mutti

    (University of Cambridge)

  • Keira Turner

    (University of Cambridge)

  • Michal Minczuk

    (University of Cambridge)

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.

Suggested Citation

  • Pedro Silva-Pinheiro & Pavel A. Nash & Lindsey Van Haute & Christian D. Mutti & Keira Turner & Michal Minczuk, 2022. "In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28358-w
    DOI: 10.1038/s41467-022-28358-w
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    References listed on IDEAS

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    1. Hyunji Lee & Seonghyun Lee & Gayoung Baek & Annie Kim & Beum-Chang Kang & Huiyun Seo & Jin-Soo Kim, 2021. "Mitochondrial DNA editing in mice with DddA-TALE fusion deaminases," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
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    Cited by:

    1. Friedrich Fauser & Bhakti N. Kadam & Sebastian Arangundy-Franklin & Jessica E. Davis & Vishvesha Vaidya & Nicola J. Schmidt & Garrett Lew & Danny F. Xia & Rakshaa Mureli & Colman Ng & Yuanyue Zhou & N, 2024. "Compact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Ason C. Y. Chiang & Jan Ježek & Peiqiang Mu & Ying Di & Anna Klucnika & Martin Jabůrek & Petr Ježek & Hansong Ma, 2024. "Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Haifeng Sun & Zhaojun Wang & Limini Shen & Yeling Feng & Lu Han & Xuezhen Qian & Runde Meng & Kangming Ji & Dong Liang & Fei Zhou & Xin Lou & Jun Zhang & Bin Shen, 2023. "Developing mitochondrial base editors with diverse context compatibility and high fidelity via saturated spacer library," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Julian C. W. Willis & Pedro Silva-Pinheiro & Lily Widdup & Michal Minczuk & David R. Liu, 2022. "Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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