Therapeutic Gene Editing for Hemoglobinopathies

Abstract

In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding β-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases.

Keywords: Gene editing; Hemoglobinopathies; Sickle Cell Anemia; Thalassemia; gene therapy.

Figure 1

Schematic representation of the transcription factor binding sites in the erythroid enhancer region located in intron 2 of the BCL11A gene. The binding of the GATA1 transcription factor increases the BCL11A expression, resulting in a decreased expression of γ-globin gene. Disruption of the erythroid-specific enhancer of BCL11A by gene editing determines an increased expression of γ-globin and HbF production. This approach is an effective therapeutic strategy for the treatment of β-thal and SCD patients.

Figure 2

Control of γ-globin gene expression mediated by BCL11A. Top panel: nucleotide sequence of the gene promoter of HBG1 and HBG2 genes; in these promoters are present to BCL11A TGACCA binding sites (a distal −118 to −113 and a proximal −91 to −86). Middle panel: the distal site actively binds BCL11A in adult erythroid cells and represses γ-globin gene expression. Bottom panel: disruption of the distal BCL11A binding site by gene editing derepress γ-globin expression and can be therapeutically exploited in β-thal and SCD patients.