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In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice

Author

Listed:
  • Alice Rovai

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research)

  • BoMee Chung

    (Hannover Medical School)

  • Qingluan Hu

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research)

  • Sebastian Hook

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research)

  • Qinggong Yuan

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research)

  • Tibor Kempf

    (Hannover Medical School)

  • Florian Schmidt

    (Department of Biosystems Science and Engineering, ETH Zürich
    University of Heidelberg, Cluster of Excellence CellNetworks
    University of Heidelberg)

  • Dirk Grimm

    (University of Heidelberg, Cluster of Excellence CellNetworks
    University of Heidelberg
    partner site Heidelberg)

  • Steven R. Talbot

    (Hannover Medical School)

  • Lars Steinbrück

    (Hannover Medical School)

  • Jasper Götting

    (Hannover Medical School)

  • Jens Bohne

    (Hannover Medical School)

  • Simon A. Krooss

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research
    Hannover Medical School)

  • Michael Ott

    (Hannover Medical School
    Twincore Centre for Experimental and Clinical Infection Research)

Abstract

Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans.

Suggested Citation

  • Alice Rovai & BoMee Chung & Qingluan Hu & Sebastian Hook & Qinggong Yuan & Tibor Kempf & Florian Schmidt & Dirk Grimm & Steven R. Talbot & Lars Steinbrück & Jasper Götting & Jens Bohne & Simon A. Kroo, 2022. "In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32906-9
    DOI: 10.1038/s41467-022-32906-9
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    References listed on IDEAS

    as
    1. Nicole M. Gaudelli & Alexis C. Komor & Holly A. Rees & Michael S. Packer & Ahmed H. Badran & David I. Bryson & David R. Liu, 2017. "Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage," Nature, Nature, vol. 551(7681), pages 464-471, November.
    Full references (including those not matched with items on IDEAS)

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