Ngo Duyen A, Steinberg Martin H
Department of Medicine, Boston University School of Medicine, 820 Harrison Ave., FGH 1st Floor, Boston, MA, 02118, USA.
Departments of Medicine, Pediatrics, Pathology and Laboratory Medicine, Boston University School of Medicine, 72 E. Concord Street, Boston, MA, 02118, USA.
BMC Med Genomics. 2015 Jul 29;8:44. doi: 10.1186/s12920-015-0120-2.
Sickle cell disease and β thalassemia are common severe diseases with little effective pathophysiologically-based treatment. Their phenotypic heterogeneity prompted genomic approaches to identify modifiers that ultimately might be exploited therapeutically. Fetal hemoglobin (HbF) is the major modulator of the phenotype of the β hemoglobinopathies. HbF inhibits deoxyHbS polymerization and in β thalassemia compensates for the reduction of HbA. The major success of genomics has been a better understanding the genetic regulation of HbF by identifying the major quantitative trait loci for this trait. If the targets identified can lead to means of increasing HbF to therapeutic levels in sufficient numbers of sickle or β-thalassemia erythrocytes, the pathophysiology of these diseases would be reversed. The availability of new target loci, high-throughput drug screening, and recent advances in genome editing provide the opportunity for new approaches to therapeutically increasing HbF production.
镰状细胞病和β地中海贫血是常见的严重疾病，基于病理生理学的有效治疗方法很少。它们的表型异质性促使采用基因组学方法来识别最终可能用于治疗的修饰因子。胎儿血红蛋白（HbF）是β血红蛋白病表型的主要调节因子。HbF抑制脱氧HbS聚合，在β地中海贫血中可补偿HbA的减少。基因组学的主要成功在于通过识别该性状的主要数量性状位点，更好地理解了HbF的遗传调控。如果所确定的靶点能够使足够数量的镰状细胞或β地中海贫血红细胞中的HbF增加到治疗水平，这些疾病的病理生理学将得到逆转。新靶点的出现、高通量药物筛选以及基因组编辑的最新进展为治疗性增加HbF产生的新方法提供了机会。
