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

β-thalassemia is one of the most common genetic diseases worldwide and is caused by mutations affecting β-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 the 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 a safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent β-thalassemic mutations [IVS1-110 (G>A)] using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to ~80% of gene correction in β-thalassemic patients' HSPCs without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore β-globin production and correct inefficient erythropoiesis typically observed in β-thalassemia 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 β-thalassemia.