beta-Thalassemia (BT) is one of the most common genetic diseases worldwide and is caused by mutations affecting beta-globin production. The only curative treatment is allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited by compatible donor availability and immunological complications. Therefore, transplantation of autologous, genetically-modified HSPCs is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors are not equally effective in all patients and CRISPR/Cas9 nuclease-based strategies raise safety concerns. Thus, base editing strategies aiming to correct the genetic defect in patients' HSPCs could provide safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent BT mutations (IVS1-110 [G>A]) using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to similar to 80% of gene correction in the HSPCs of patients with BT without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore beta-globin production and correct inefficient erythropoiesis typically observed in BT both in vitro and in vivo. In conclusion, this proof-of-concept study paves the way for the development of a safe and effective autologous gene therapy approach for BT.

Adenine base editor-mediated correction of the common and severe IVS1-110 (G>A) β-thalassemia mutation / Hardouin, Giulia; Antoniou, Panagiotis; Martinucci, Pierre; Felix, Tristan; Manceau, Sandra; Joseph, Laure; Masson, Cécile; Scaramuzza, Samantha; Ferrari, Giuliana; Cavazzana, Marina; Miccio, Annarita. - In: BLOOD. - ISSN 1528-0020. - 141:10(2023), pp. 1169-1179. [10.1182/blood.2022016629]

Adenine base editor-mediated correction of the common and severe IVS1-110 (G>A) β-thalassemia mutation

Ferrari, Giuliana;
2023-01-01

Abstract

beta-Thalassemia (BT) is one of the most common genetic diseases worldwide and is caused by mutations affecting beta-globin production. The only curative treatment is allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited by compatible donor availability and immunological complications. Therefore, transplantation of autologous, genetically-modified HSPCs is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors are not equally effective in all patients and CRISPR/Cas9 nuclease-based strategies raise safety concerns. Thus, base editing strategies aiming to correct the genetic defect in patients' HSPCs could provide safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent BT mutations (IVS1-110 [G>A]) using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to similar to 80% of gene correction in the HSPCs of patients with BT without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore beta-globin production and correct inefficient erythropoiesis typically observed in BT both in vitro and in vivo. In conclusion, this proof-of-concept study paves the way for the development of a safe and effective autologous gene therapy approach for BT.
2023
Gene Therapy, Red Cells, Iron, Erythropoiesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/162036
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