More disease-modifying therapies for sickle cell disease: Are small molecules and drug repurposing the way forward?

Despite advances in understanding the molecular and cellular pathophysiology of sickle cell disease (SCD), the development of effective pharmacologic therapies has been slow. Hydroxyurea, a small molecule repurposed decades ago, remains the cornerstone of disease-modifying therapy, and it is the benchmark against which new therapies are measured. Recent approvals of additional agents have expanded therapeutic options, yet their clinical benefits have been narrow, sometimes uncertain, or complicated by regulatory withdrawals, underscoring the persistent challenges of translating biologically plausible mechanisms into clinical benefits. The central pathogenic event in SCD, the polymerization of deoxygenated sickle hemoglobin (Hb), initiates a cascade of red blood cell (RBC) injury, hemolysis, vaso-occlusion, vasculopathy, inflammation, and progressive organ damage. Drugs that act proximally in this pathway are more likely to be broadly effective. Small molecules, in particular, are appealing because of oral bioavailability, ability to enter RBCs, and scalability in manufacturing. In parallel to development of new agents, drug repurposing can accelerate the process of drug development by using agents with known pharmacologic and safety profiles. This review highlights recent and emerging disease-modifying approaches for SCD, with emphasis on small molecules and repurposed drugs, including pyruvate kinase activators, epigenetic fetal hemoglobin inducers, Hb oxygen-affinity modulators, and iron restriction strategies. Each therapy addresses distinct yet interconnected aspects of SCD pathophysiology. No single therapy is likely to be completely protective across the lifespan. The future of SCD pharmacotherapy will likely include mechanism-based combination therapies concurrent with the advancements in genetic and cellular therapies.