Base editing approaches for correcting the ivs2-1...

Abstract

IVS2-1 (G>A) is one of the most common β0-thalassemic mutations in the Middle East3. This point mutation occurs at the first nucleotide of the second intron of HBB and disrupts the splice donor site. It results in the production of two abnormally spliced mRNAs4. The first mRNA is characterized by a partial retention of the second intron, whereas the second mRNA consists of the first exon spliced directly with the third one. Importantly, none of them lead to the production of β-globin. Here, the inventors exploited adenine base-editors (ABEs) to correct the IVS2-1 (G>A) mutation in HSPCs from β-thalassemia patients and demonstrated the potential of this strategy to correct the pathological phenotype observed during erythroid differentiation. In particular the inventors demonstrated that reverting the IVS2-1 (G>A) mutation using base editing corrected in vitro the β-thalassemic cell phenotype in terms of erythroid differentiation, enucleation, RBC size and apoptosis. The present invention thus relates to base editing approaches for the treatment of β-thalassemia, including sickle β-thalassemia.

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