Abstract：
Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.
摘要：
意义：镰状细胞病（SCD）是影响全球大多数服务不足人群的最常见的遗传素质。SCD的特点是慢性疼痛和疲劳，需要住院治疗和阿片类药物的严重急性疼痛危机，笔画,多器官损伤,寿命缩短。症状可能在出生后不久出现，and,在欠发达国家,大多数患有SCD的儿童在5岁之前死亡。造血干细胞移植和基因治疗提供了治愈性治疗方法，但是,由于许多挑战，对于大多数SCD患者，其可用性和有效性有限。一个关键的未满足的需求是开发安全有效的新型靶向疗法。目前正在进行临床研究的各种药物有望扩大抗SCD的药理药库。最新进展：羟基脲，最广泛使用的SCD管理干预措施，改善了西方世界的生存，最近，voxelotor（R状态稳定器），l-谷氨酰胺,和crizanlizumab（抗P-选择素抗体）已被食品和药物管理局（FDA）批准用于SCD。最近的FDA批准强调需要重新审视在理解SCD的核心病理生理学方面的进展，以加速新的循证治疗SCD的策略。红细胞分解的生物力学破坏，SCD的核心病理生理学，与内在因素有关，包括血红蛋白的组成，膜完整性,细胞体积,水合作用,和氧化应激。关键问题和未来方向：在这种情况下，这篇综述的重点是针对镰状红细胞（RBC）固有的治疗靶标的新兴非遗传干预措施的进展，这可以防止红细胞流变性受损，以阻止疾病进展并减少合并症的后遗症，包括疼痛,血管病变,和器官损伤。此外,鉴于这种疾病复杂的病理生理学，单一药物治疗干预不可能全面改善与SCD相关的多方面并发症.然而,多种药物选择的可用性为针对特定SCD相关并发症量身定制的个体化治疗方案提供了机会.此外，它为联合药物治疗开辟了道路，利用不同的作用机制和不良反应的概况。
