Base editing of β0 thalassemia mutations as a therapeutic strategy for β-hemoglobinopathies: efficacy and genotoxicity studies

Gene therapy has emerged as a promising curative treatment for {beta}-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 editors (ABE) variants to precisely correct some of the most prevalent and severe {beta}-thalassemia-causing mutations in the {beta}-globin gene. Efficient editing of hematopoietic stem/progenitor cells (HSPCs) led to potent {beta}-globin expression in their erythroid progeny and persistent correction of both {beta}-thalassemia and sickle cell-{beta}-thalassemia phenotypes. Safety of this strategy was confirmed in HSPCs in vitro and in vivo by the absence of gene dysregulation or any meaningful impact on the DNA mutational burden, the RNA deamination level, the {beta}-globin gene locus integrity and the clonality of the HSPC graft. Overall, base editing-mediated gene correction is a safe and effective strategy for treating {beta}-hemoglobinopathies. One sentence summaryPreclinical safety and efficacy studies of a new gene therapy approach for patients with severe {beta}-hemoglobinopathies.