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Direct correction of haemoglobin E β-thalassaemia using base editors

Author

Listed:
  • Mohsin Badat

    (University of Oxford
    Royal London Hospital, Barts Health NHS Trust)

  • Ayesha Ejaz

    (University of Oxford)

  • Peng Hua

    (University of Oxford
    Nanjing Medical University)

  • Siobhan Rice

    (University of Oxford)

  • Weijiao Zhang

    (University of Oxford)

  • Lance D. Hentges

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Christopher A. Fisher

    (University of Oxford)

  • Nicholas Denny

    (University of Oxford)

  • Ron Schwessinger

    (University of Oxford)

  • Nirmani Yasara

    (University of Kelaniya)

  • Noemi B. A. Roy

    (University of Oxford)

  • Fadi Issa

    (University of Oxford)

  • Andi Roy

    (University of Oxford
    University of Oxford)

  • Paul Telfer

    (Royal London Hospital, Barts Health NHS Trust)

  • Jim Hughes

    (University of Oxford
    University of Oxford)

  • Sachith Mettananda

    (University of Kelaniya)

  • Douglas R. Higgs

    (University of Oxford)

  • James O. J. Davies

    (University of Oxford
    Royal London Hospital, Barts Health NHS Trust
    National Institute of Health Research Blood and Transplant Research Unit in Precision Cellular Therapeutics)

Abstract

Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due to a point mutation in codon 26 of the human HBB gene on one allele (GAG; glutamatic acid → AAG; lysine, E26K), and any mutation causing severe β-thalassaemia on the other. When inherited together in compound heterozygosity these mutations can cause a severe thalassaemic phenotype. However, if only one allele is mutated individuals are carriers for the respective mutation and have an asymptomatic phenotype (β-thalassaemia trait). Here we describe a base editing strategy which corrects the HbE mutation either to wildtype (WT) or a normal variant haemoglobin (E26G) known as Hb Aubenas and thereby recreates the asymptomatic trait phenotype. We have achieved editing efficiencies in excess of 90% in primary human CD34 + cells. We demonstrate editing of long-term repopulating haematopoietic stem cells (LT-HSCs) using serial xenotransplantation in NSG mice. We have profiled the off-target effects using a combination of circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) and deep targeted capture and have developed machine-learning based methods to predict functional effects of candidate off-target mutations.

Suggested Citation

  • Mohsin Badat & Ayesha Ejaz & Peng Hua & Siobhan Rice & Weijiao Zhang & Lance D. Hentges & Christopher A. Fisher & Nicholas Denny & Ron Schwessinger & Nirmani Yasara & Noemi B. A. Roy & Fadi Issa & And, 2023. "Direct correction of haemoglobin E β-thalassaemia using base editors," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37604-8
    DOI: 10.1038/s41467-023-37604-8
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    References listed on IDEAS

    as
    1. Gregory A. Newby & Jonathan S. Yen & Kaitly J. Woodard & Thiyagaraj Mayuranathan & Cicera R. Lazzarotto & Yichao Li & Heather Sheppard-Tillman & Shaina N. Porter & Yu Yao & Kalin Mayberry & Kelcee A. , 2021. "Base editing of haematopoietic stem cells rescues sickle cell disease in mice," Nature, Nature, vol. 595(7866), pages 295-302, July.
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