镰状细胞病：治愈触手可及，正义仍遥遥无期

By Abdirazak Mohamed and Athanasia Agapiou Sickle Cell Disease:ACure Within Reach, Justice Still Distant Introduction Sickle cell disease (SCD) is a monogenicinherited blood disorder, characterized byabnormal hemoglobin in red blood cells. Oxygenis carried throughout the body via hemoglobinand a missense mutation in theβ-globin generesults in a defective sickle-like form. This causesthe formation of insoluble hemoglobin polymersand impairing of red blood cell membrane andultimately leads to sickled erythrocytes. Thesecrescent-shaped red blood cells impede bloodflow as they are prone to clustering, restrictingoxygen delivery to tissues and leading toextreme pain and even organ damage, knownas vaso-occlusive events or crises. This isjust the hallmark of the disease; additionalsymptoms include increased susceptibilityto infections, anemia, and in severe cases,premature death.1 sickle cell trait, which is the possession of onecopy of the sickle cell gene, provided someprotection against severe malaria in areassuch as Africa, where the disease is common.Many of African descent came to the UScarrying the sickle cell gene with them. SCDcan be crippling, and healthcare demandshave been historically undelivered.3 The therapeutic landscape for SCD has evolvedsignificantly between 1995 and 2025, markedby long periods of stagnation followed bybursts of innovation. Over the span of 22 years(1995–2017), only two drugs were launched,niprisan and piracetam. A wave of renewedmomentum followed between 2018 and 2022,with the approvals of L-glutamine, voxelotor,and crizanlizumab expanding treatmentoptions for patients. Since 2023, the field hasentered the gene therapy era with the landmarkapprovals of Casgevy and Lyfgenia. As of 2025,six drugs have been launched for SCD, but thetotal was reduced following Pfizer’s withdrawalof voxelotor (Figure 1). The condition is prevalent, with 8 million peopleaffected worldwide and 107,182 of thoseindividuals currently living in the US,2most ofwhom are of African descent. This prevalenceis believed to be because of the evolutionaryadvantage it offered against malaria. The Source: Pharmaprojects, May 2025 Sickle Cell Disease:ACure Within Reach, Justice Still Distant Current therapies and emerging scientificadvances The current SCD drug development landscapecomprises 63 known candidates (Figure 2), yetonly seven therapies have achieved regulatoryapproval to date. Nearly half the pipelineremains in preclinical development, withapproximately a quarter in Phase II trials. Farfewer candidates have progressed into Phase III or regulatory submission.4As will beexplored in greater detail later, this slowprogression reflects intersecting challengesincluding scientific complexity, limitedmarket incentives, and systemic inequitiesthat have historically impeded innovationin SCD therapies. Sickle Cell Disease:ACure Within Reach, Justice Still Distant Traditional approaches include painmanagement, blood transfusions, andhydroxyurea, focusing primarily on symptomrelief and preventing complications rather thanaddressing the underlying cause. Hydroxyurea iswidely recognized as the most extensively useddisease-modifying therapy for SCD, reducingsickle cell crises and mortality rates.1 vaso-occlusive crises (VOCs); however, its long-term efficacy following the terminated STANDtrial led to its market withdrawals in Europe andthe UK.6 The approval of gene therapies Casgevy andLyfgenia in 2023 marked a historic milestoneand hopeful paradigm shift, offering thefirst durable, one-time treatments thattarget the root cause of SCD. Casgevy,developed by CRISPR Therapeutics and VertexPharmaceuticals, employs CRISPR/Cas9 todisrupt the BCL11A enhancer, reactivating fetalhemoglobin (HbF) production. Meanwhile,Lyfgenia, developed by Bluebird Bio, uses alentiviral vector to insert a functionalβ-globingene. Both therapies significantly reducedVOCs and hospitalizations in clinical trials,representing a turning point from symptommanagement to potential cure.7 In recent years, the treatment landscapefor SCD has expanded beyond traditionaltherapies to include targeted agents with novelmechanisms of action. Oxbryta (voxelotor) andAdakveo (crizanlizumab), both approved in2019, exemplified this shift. Oxbryta inhibitedhemoglobin S polymerization to treat chronicanemia but was voluntarily withdrawn in 2024after emerging data raised concerns about itsbenefit-risk profile.5Adakveo, a monoclonalantibody targeting P-selectin, aimed to reduce Sickle Cell Disease:ACure Within Reach, Justice Still Distant While the global pipeline for SCD therapiesis growing, drug development remainsgeographically concentrated. As shown inFigure 3, the US leads with 47 SCD drugsin active development, more than triple thenumber in the UK (15), followed by Canadaand France (10 each). Other countries includeItaly (eight), Lebanon (seven), and China,Germany, Kenya, and Spain (six each). Despite sub-Saharan Africa bearing the greatest SCDburd