CRISPR/Cas9 Editing of the β-Globin Locus in Sickle Cell Disease and β-Thalassemia: Mechanistic Rationale, Clinical Evidence, and Future Directions

Sickle cell disease (SCD) and β‑thalassemia rank among the world’s most frequent single-gene disorders and remain the leading causes of illness and early death, even with better supportive care. Both conditions stem from harmful mutations in the β‑globin gene (HBB) and are prime candidates for gene-editing therapies, as fetal hemoglobin (HbF) can greatly reduce disease severity. This review first explains the molecular basis of β-hemoglobinopathies and the processes that govern Hb switching, focusing on BCL11A, HBG1/HBG2 promoters, and α-globin as therapeutic targets. This review then examined CRISPR/Cas9 techniques and delivery methods used to edit hematopoietic stem and progenitor cells outside the body, contrasting direct HBB correction with approaches that reactivate HbF and with new multiplex editing strategies. Clinical data from therapies targeting the BCL11A enhancer or the HBG promoter in patients with SCD and transfusion-dependent β‑thalassemia are reviewed, highlighting high rates of transfusion independence, marked reductions in vaso-occlusive crises, and safety primarily limited by conditioning-related toxicity. The article also discusses genomic risks, ethical concerns, cost, and access challenges, and suggests future avenues, such as base and prime editing, in vivo delivery, and safer conditioning regimens. In summary, CRISPR-based editing of the β-globin locus offers a realistic functional cure for selected patients, while underscoring the need for long-term follow-up and fair global implementation. HIGHLIGHTS The molecular basis of β-hemoglobinopathies and identifies key regulatory targets in the β-globin locus for CRISPR/Cas9 therapy. Major CRISPR/Cas9 strategies, including HBB correction, BCL11A enhancer disruption, HBG1/HBG2 promoter editing, and α-globin modulation, in the context of sickle cell disease and β-thalassemia. Integrating and critically evaluating clinical trial data for ex vivo edited hematopoietic stem cell products, highlighting transfusion independence, vaso-occlusive crisis reduction, and emerging safety signals. Genomic, ethical, and health-system challenges, including off-target risk, conditioning-related toxicity, cost, and global equity of access to gene-editing therapies, are analyzed. Outlines future directions, such as base and prime editing, in vivo delivery platforms, and safer conditioning regimens, to guide next-generation therapies for β-hemoglobinopathies. GRAPHICAL ABSTRACT