Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Irving Medical Center, Children's Hospital North 10th Floor, Room 10-09 A3959 Broadway, New York, NY 10032, USA.
Center for Sickle Cell Disease, The University of Tennessee Health Science Center, Department of Medicine-Hematology, 880 Madison Avenue, Memphis, TN 38103, USA.
Transfus Apher Sci. 2022 Oct;61(5):103555. doi: 10.1016/j.transci.2022.103555. Epub 2022 Aug 29.
Sickle cell disease is an inherited blood disorder afflicting an estimated 100,000 individuals in the United States and over 20 million people worldwide. The disease is heralded as the first molecular disease. However, despite its genetic simplicity, the pathophysiologic processes leading to its clinical sequelae are complex, heterogeneous and interrelated, making drug development to treat the disease challenging. For over two decades only one drug, hydroxyurea, had been used as disease-modifying therapy. New pharmacologic agents are rapidly evolving with three new drugs, with different mechanisms of action, approved by the United States Food and Drug Administration in recent years (L-glutamine, crizanlizumab and voxelotor). Several therapeutic approaches targeting different pathways in the disease pathophysiology are being investigated. These include inhibition of hemoglobin S polymerization such as by fetal hemoglobin induction or by increasing hemoglobin oxygen affinity, as well as intervention of downstream pathways including inhibiting cellular adhesion, reducing inflammation and oxidant stress, modulating platelet activation and coagulation abnormalities, and targeting nitric oxide signaling. This review will provide an overview of these therapeutic strategies, discuss the four currently approved drugs in detail, and summarize ongoing clinical trials of new drugs or drug indications for the treatment of sickle cell disease in different phases of development excluding those related to cellular therapies.
镰状细胞病是一种遗传性血液疾病，估计在美国有 10 万人患有这种疾病，在全球有超过 2000 万人患有这种疾病。该病被称为第一个分子疾病。然而，尽管其遗传结构简单，但导致其临床后果的病理生理过程却很复杂、异质且相互关联，这使得治疗该病的药物研发具有挑战性。二十多年来，只有一种药物——羟基脲——被用作疾病修正治疗。近年来，三种具有不同作用机制的新型药物（L-谷氨酰胺、crizanlizumab 和 voxelotor）已被美国食品和药物管理局批准用于治疗该病。目前正在研究针对该病病理生理学不同途径的多种治疗方法。这些方法包括抑制血红蛋白 S 聚合，如诱导胎儿血红蛋白或增加血红蛋白氧亲和力，以及干预下游途径，包括抑制细胞黏附、减少炎症和氧化应激、调节血小板激活和凝血异常，以及靶向一氧化氮信号。本文将概述这些治疗策略，详细讨论目前批准的四种药物，并总结正在进行的新药临床试验或不同开发阶段（不包括与细胞疗法相关的药物）用于治疗镰状细胞病的新药物或药物适应证。
