Precision Medicine in Sickle Cell Disease: From Molecular Pathways to Curative Strategies.

Abstract

Sickle cell disease (SCD) is a monogenic β-globin disorder characterized by hemoglobin S polymerization, hemolysis, and vaso-occlusion, yet it exhibits remarkable clinical heterogeneity. Despite advances in supportive care and disease-modifying therapies, substantial variability in severity, treatment response, and long-term outcomes persists. Therefore, this review aims to examine the biological and clinical foundations of precision medicine in SCD, emphasizing genomic modifiers, molecular pathways, and phenotype-driven therapeutic strategies. Key pathogenic pathways including hemoglobin polymerization, vascular adhesion, and inflammatory and oxidative amplification have enabled the development of targeted agents such as hydroxyurea, voxelotor, crizanlizumab, and L-glutamine, each demonstrating domain-specific targets. Pharmacogenomic insights, particularly involving fetal hemoglobin regulatory loci (e.g. BCL11A and HBS1L-MYB), further elucidate variability in disease expression and therapeutic response. Emerging curative approaches, including allogeneic hematopoietic stem cell transplantation, lentiviral gene addition, and CRISPR-Cas9-mediated genome editing, represent transformative applications of precision hematology. Collectively, these advances support a paradigm shift from generalized symptom management toward biologically informed, individualized care. Continued integration of genomic profiling, biomarker stratification, and equitable implementation frameworks will be essential to translate precision strategies into sustainable improvements in global SCD outcomes.