Direct correction of haemoglobin E β-thalassaemia using base editors

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, Andi Roy, Paul Telfer, Jim Hughes, Sachith Mettananda, Douglas R. Higgs and James O. J. Davies ()
Additional contact information
Mohsin Badat: University of Oxford
Ayesha Ejaz: University of Oxford
Peng Hua: University of Oxford
Siobhan Rice: University of Oxford
Weijiao Zhang: University of Oxford
Lance D. Hentges: 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
Paul Telfer: Royal London Hospital, Barts Health NHS Trust
Jim Hughes: University of Oxford
Sachith Mettananda: University of Kelaniya
Douglas R. Higgs: University of Oxford
James O. J. Davies: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-7

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37604-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37604-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37604-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().