A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease

Fetal hemoglobin reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime editing strategy that introduces multiple mutations in the fetal γ-globin promoters that are expected to increase their activity. We tested multiple targets and optimized a variety of parameters to achieve ∼50% of precise edits in a hematopoietic cell line, with minimal off-target effects. This work improved our understanding of the complex DNA repair mechanisms involved in prime editing. We tested this strategy in patients' hematopoietic stem/progenitor cells. Although editing efficiency was variable among donors, erythroid clones carrying multiple mutations expressed a significantly higher γ-globin level than cells carrying individual mutations, confirming the potential therapeutic benefit of our combined strategy for patients with β-hemoglobinopathies.

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Publication Details

Journal
Blood
Published
2025-08-26
DOI
https://doi.org/10.1182/blood.2024028166
Citations
3
Primary Topic
Hemoglobinopathies and Related Disorders
Type
article
Field-Weighted Citation Impact
4.88
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article

A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease

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3 citations
Blood
Hemoglobinopathies and Related Disorders
4.88
article

A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease

Annarita Miccio, Letizia Fontana, Anne Chalumeau, Margaux Mombled, Simone Amistadi, Mégane Brusson, Carine Giovannangeli, Marcello Maresca, Mario Amendola, Guillaume Corre, Panagiotis Antoniou, Martin Peterka, P. Loganathan, Maria Bou Dames
article en
3 citations

Abstract

Fetal hemoglobin reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime editing strategy that introduces multiple mutations in the fetal γ-globin promoters that are expected to increase their activity. We tested multiple targets and optimized a variety of parameters to achieve ∼50% of precise edits in a hematopoietic cell line, with minimal off-target effects. This work improved our understanding of the complex DNA repair mechanisms involved in prime editing. We tested this strategy in patients' hematopoietic stem/progenitor cells. Although editing efficiency was variable among donors, erythroid clones carrying multiple mutations expressed a significantly higher γ-globin level than cells carrying individual mutations, confirming the potential therapeutic benefit of our combined strategy for patients with β-hemoglobinopathies.

BloodVol. 146(22)
University of Foggia (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Université Paris-Saclay (FR), AstraZeneca (Netherlands) (NL), Muséum national d'Histoire naturelle (FR), Genethon (France) (FR), AstraZeneca (Japan) (JP), AstraZeneca (Finland) (FI), Institut des Maladies Génétiques Imagine (FR), Université d'Évry Val-d'Essonne (FR)
Openalex Percentile: Top 5%
Hemoglobinopathies and Related Disorders
4.88
DOIOpen Access PDFOpenAlex
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