Hemoglobinopathies such as sickle cell disease (SCD) and beta (β)-thalassemia are inherited disorders characterized by defective or insufficient β-globin chain production, resulting in chronic anemia, multi-organ damage, and reduced life expectancy. Affecting millions worldwide, particularly in sub-Saharan Africa, the Mediterranean, South Asia, the Middle East, and the Caribbean, these conditions represent the most common monogenic diseases globally. Traditional treatments, including blood transfusions and hydroxyurea, offer limited long-term benefit, while allogeneic bone marrow transplantation is curative but constrained by donor availability and procedural risks. In recent years, gene therapy and genome editing technologies have emerged as transformative tools, offering the potential for durable, patient-specific cures. This chapter reviews the underlying molecular mechanisms of SCD and β-thalassemia and explores current gene therapy approaches, including lentiviral gene addition and CRISPR-Cas9-mediated editing. A major focus is on reactivation of fetal hemoglobin (HbF) through targeted disruption of transcriptional repressors such as BCL11A. Clinical trial outcomes are examined alongside European Union (EU), United States of America (USA), and United Kingdom (UK) approved therapies such as Casgevy, Lyfgenia, and Zynteglo, highlighting both the therapeutic promise and real-world challenges, including myeloablative toxicity, access disparities, and infrastructure limitations. The chapter also emphasizes the global dimension of hemoglobinopathies and the urgent need for equitable implementation strategies, especially in resource-limited settings. Integrating insights from molecular genetics, clinical research, and global health policy, this chapter provides a comprehensive and up-to-date synthesis of genome editing advances and their application in curing SCD and β-thalassemia.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy in which hemoglobin S (HbS) polymerizes on deoxygenation, leading to sickling of red blood cells (RBCs) and driving the acute vaso-occlusive crisis (VOC). With curative (transformative) therapies inaccessible to most patients in sub-Saharan Africa and the Caribbean, where burden is highest, optimizing acute VOC care is a priority; yet oxygen is given reactively, after hypoxemia is documented, not at symptom onset when polymerization is most interruptible. We conducted a structured narrative review integrating HbS polymerization kinetics, clinical studies of oxygen-based therapies, trial protocols, and home-care implementation evidence (PubMed, Scopus, Google Scholar; 1974–2026). When RBCs release oxygen, HbS does not solidify at once: a brief pause, the nucleation delay phase (t_D), precedes polymerization and sickling. Because t_D falls steeply as deoxygenated hemoglobin rises (inversely, to its ~30th–50th power), a small early gain in oxygen saturation (~5–10%) lengthens it many-fold, opening a short window, roughly 30 min from onset, during which oxygen may abort a crisis. The clinical message is that timing, not dose, is decisive: oxygen at the first symptoms may prevent a crisis that the same oxygen, given later, cannot. Standard, high-flow, hyperbaric, and inhaled nitric-oxide modalities help in selected hospital settings, and the DREPADOM model shows community delivery before hospital arrival is feasible and safe. The central argument is precision in timing, not quantity: starting oxygen at symptom onset could turn a low-cost, universally available treatment into a crisis-aborting one for patients beyond the reach of curative therapy. We advance this as a mechanistically grounded but clinically untested hypothesis; regional implementation trials in the Caribbean and sub-Saharan Africa are urgently warranted.

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes and distorts erythrocytes into the characteristic sickle shape, initiating a cascade of vaso-occlusion, chronic hemolytic anemia, and progressive multi-organ damage that defines the clinical burden of this disease. Although SCD has ancient origins in sub-Saharan Africa, the Indian subcontinent, the Middle East, and the Mediterranean, regions where it conferred heterozygous resistance to malaria, the ease of human migration has long since made it a global health concern, affecting an estimated 300,000–400,000 newborns annually. Advances in molecular and genomic research have deepened our understanding of SCD pathophysiology, revealing the central contributions of hemoglobin polymerization, oxidative stress, endothelial inflammation, and nitric oxide depletion to disease progression. Current management rests on supportive pharmacological interventions, including hydroxyurea, chronic transfusion therapy, L-glutamine, and multimodal pain management, complemented by lifestyle modifications. Curative approaches have advanced substantially: hematopoietic stem cell transplantation (HSCT) remains the established standard of cure, while the regulatory approvals in late 2023 of the CRISPR/Cas9-based exagamglogene autotemcel (Casgevy) and the lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia) represent the most transformative development in the history of SCD therapeutics. This review traces the disease from its ancient origins and molecular characterization through to its clinical manifestations, inheritance patterns, screening strategies, and the full spectrum of current and emerging therapies. Persistent challenges, prohibitive treatment costs, healthcare inequities, the ethical dimensions of genome editing, and the urgent need for long-term safety data, are examined critically, with a view to informing the research and policy agenda that must accompany these remarkable scientific advances.