Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of North Carolina Chapel Hill School of Medicine.
Department of Medicine, Division of Hematology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Haematologica. 2019 Sep;104(9):1710-1719. doi: 10.3324/haematol.2018.207357. Epub 2019 Aug 14.
Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways 'downstream' to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute's 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplantation in approximately 1,000 people, most of whom were children, and significantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of multimodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibition of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation proteins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sickle cell disease currently, or recently, tested in clinical trials in the era following approval of hydroxyurea.
镰状细胞病影响全球数百万人，约 10 万美国人。并发症众多，是 DNA 点突变下游复杂病理途径的结果，包括红细胞膜损伤、炎症、慢性溶血性贫血伴间歇性血管阻塞、缺血和疼痛，最终导致累积器官损伤，受影响个体的寿命缩短。美国国立心肺血液研究所 2014 年镰状细胞病管理循证指南指出，在 investigational curative 疗法广泛应用于大多数镰状细胞病患者之前，还需要更多的研究。迄今为止，大约有 1000 人通过造血干细胞移植治愈了镰状细胞病，其中大多数是儿童，少数人通过基因治疗显著改善了镰状细胞病，而这些人目前的随访时间有限。在食品和药物管理局批准了 20 多种治疗囊性纤维化的药物的这段时间里，只有两种药物（羟基脲和 L-谷氨酰胺）被批准用于治疗镰状细胞病，尽管镰状细胞病的发病率更高。这种情况似乎正在发生变化，因为镰状细胞病缺乏多模式药物治疗，促使学术界和工业界的许多人参与其中，在过去十年中，他们开发了新的药物，旨在预防并发症和缓解痛苦。确定的治疗策略包括诱导胎儿血红蛋白、抑制细胞内 HbS 聚合、抑制氧化应激和炎症，以及干扰内皮细胞和其他参与镰状细胞病病理生理的血液成分（如血小板、白细胞、凝血蛋白）的激活。在本文中，我们简要回顾了目前或最近在羟基脲批准后的临床试验中，为镰状细胞病患者测试的疾病修正方法（不包括造血干细胞移植和基因治疗）。
