GWAS to Therapy by Genome Edits?

摘要

Disorders of hemoglobins are the most common monogenic diseases in the world, with substantial morbidity and mortality resulting from either defective function of the protein, such as in sickle cell anemia, or from insufficient protein production, such as the thalassemias (1). Genome-wide association studies (GWAS) have implicated two genes other than the globin genes as potential modulators of the pathology of these diseases by influencing the amounts of fetal hemoglobin (HbF). On page 253 in this issue, Bauer et al. (2) characterize common single-nucleotide polymorphisms (SNPs) in one of these genes, BCL11A. SNPs associated with mild increases in HbF amounts reside within a powerful tissue- and developmental stage-specific BCL11A enhancer (see the figure). Genome engineering reveals that this enhancer is essential for erythroid expression of BCL11A, and as a consequence, for globin gene expression. This exquisite specificity points to genome editing as a plausible approach to lasting corrective cell-specific therapy for certain hemoglobinopathies.