Base editing of β <sup>0</sup> -thalassemia mutations as a therapeutic strategy for severe β-hemoglobinopathies
Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia-causing mutations in the β-globin-encoding <i>HBB</i> gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell-β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing-mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.
Authors
- Samantha Scaramuzza (ORCID: https://orcid.org/0000-0003-2903-3650)
- Annarita Miccio (ORCID: https://orcid.org/0000-0002-3409-9665)
- Alexandra Tachtsidi (ORCID: https://orcid.org/0000-0003-2155-6078)
- Margaux Mombled (ORCID: https://orcid.org/0000-0003-2704-7303)
- Giulia Hardouin (ORCID: https://orcid.org/0000-0003-2621-8975)
- Oriana Romano (ORCID: https://orcid.org/0000-0002-3483-1115)
- Eric Allemand (ORCID: https://orcid.org/0000-0002-9617-5336)
- Sandra Manceau (ORCID: https://orcid.org/0000-0003-1836-2002)
- Cécile Masson (ORCID: https://orcid.org/0000-0001-7870-7821)
- Isabelle Thuret
- Mario Amendola (ORCID: https://orcid.org/0000-0002-1188-8856)
- Guillaume Corre (ORCID: https://orcid.org/0000-0002-0755-8336)
- Pierre Martinucci (ORCID: https://orcid.org/0000-0003-3043-6457)
- Catherine Badens (ORCID: https://orcid.org/0000-0001-9024-310X)
- Panagiotis Antoniou (ORCID: https://orcid.org/0000-0002-0111-3897)
- Giuliana Ferrari (ORCID: https://orcid.org/0000-0003-0790-3133)
- Laure Joseph
- Cécile Rouillon
- Federico Corradi (ORCID: https://orcid.org/0009-0006-4926-0411)
- Sarah Szepetowsky
- Jessika Chermont
Institutions
- University of Foggia (IT)
- University of Modena and Reggio Emilia (IT)
- Centre National de la Recherche Scientifique (FR)
- University of Padua (IT)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- Université Paris-Saclay (FR)
- Assistance Publique Hôpitaux de Marseille (FR)
- Laboratory of Excellence GR-Ex (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Genethon (France) (FR)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Hôpital de la Timone (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- Université d'Évry Val-d'Essonne (FR)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1126/scitranslmed.adt8617
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00