Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype

Deborah E. Daniels, Ivan Ferrer-Vicens, Joseph Hawksworth, Tatyana N. Andrienko, Elizabeth M. Finnie, Natalie S. Bretherton, Daniel C. J. Ferguson, A. Sofia. F. Oliveira, Jenn-Yeu A. Szeto, Marieangela C. Wilson, John N. Brewin and Jan Frayne ()
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Deborah E. Daniels: University of Bristol
Ivan Ferrer-Vicens: University of Bristol
Joseph Hawksworth: University of Bristol
Tatyana N. Andrienko: University of Bristol
Elizabeth M. Finnie: University of Bristol
Natalie S. Bretherton: University of Bristol
Daniel C. J. Ferguson: University of Bristol
A. Sofia. F. Oliveira: University of Bristol
Jenn-Yeu A. Szeto: University of Bristol
Marieangela C. Wilson: University of Bristol
John N. Brewin: King’s college Hospital NHS Foundation
Jan Frayne: University of Bristol

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

Abstract: Abstract β-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular defects is impeded by paucity of suitable patient material. In this study we create human disease cellular model systems for β-thalassemia by gene editing the erythroid line BEL-A, which accurately recapitulate the phenotype of patient erythroid cells. We also develop a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilize the assay to demonstrate that the lines respond appropriately to verified reagents. We next use the lines to perform extensive analysis of the altered molecular mechanisms in β-thalassemia erythroid cells, revealing upregulation of a wide range of biological pathways and processes along with potential novel targets for therapeutic investigation. Overall, the lines provide a sustainable supply of disease cells as research tools for identifying therapeutic targets and as screening platforms for new drugs and reagents.

Date: 2023
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DOI: 10.1038/s41467-023-41961-9

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