BCL11A enhancer Knock-out: an approach for the treatment of β-thalassemia

Introduction: Beta-thalassemia is the most prevalent monogenic and hereditary blood disorder worldwide, created by a mutation in the beta-globin gene. Some experimental studies have suggested that this disease can be treated by using the induction of fetal Hemoglobin (HbF or α2γ2). Hereditary Fetal Hemoglobin (HPFH) is a benign disease in some people with high levels of fetal hemoglobin lifetime. Individuals with compound heterozygous β-thalassemia and HPFH have moderate clinical symptoms.Description: BCL11A is a transcription factor, and the regulator has been demonstrated to be embryonic and fetal globin genes silent in both mouse models and human cells, which regulates fetal hemoglobin (HbF) switching. Binding the BCL11A to the upstream Locus Control Region (LCR) lead to blocking of the interaction between the LCR and the HbF globin gene, which is essential for fetal globin expression. An erythroid-specific intronic enhancer is necessary for erythroid BCL11A expression. Fetal gamma-globin could be reactivated using genome-editing strategies such as ZFN and CRISPR-Cas9, the deletion of critical sequences and knock-out of the BCL11A enhancer in CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs).Discussion and conclusion: Clinical evidence has shown that by increasing the level of fetal hemoglobin, the severity of β-thalassemia could be alleviated. Previously, the targeted deletion of the BCL11A enhancer has been led to reactivation of gamma-globin in Κ562 cells. These findings suggest that the disruption of critical sequences within the BCL11A enhancer defined here may result in HbF levels exceeding a clinical threshold required to ameliorate the β-hemoglobin disorders. In two clinical trials, CD34+ hHSPCs was modified in the BCL11A enhancer by CRISPR-Cas9 and ZFN to treat β-thalassemic patients are currently at the recruiting process. Ultimately, this method may be a potentially curative gene therapy approach for β-hemoglobinopathies.

کلیدواژه ها:

BCL11A enhancer ، β-thalassemia ، Hereditary Fetal Hemoglobin (HPFH) ، CRISPR-Cas9