CRISPR-Based Genome Editing in Sickle Cell Disease: Navigating the Transition from Molecular Triumph to Pediatric Expansion

Sickle cell disease (SCD) is the most prevalent severe monogenic disorder worldwide, historically defined by lifelong symptom management. The advent of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) genome editing has initiated a paradigm shift from disease modulation to definitive molecular correction. This review synthesizes the trajectory of CRISPR-based therapies for SCD, from the molecular rationale of B-cell lymphoma/leukemia 11A (BCL11A) erythroid enhancer disruption to the clinical realization of exagamglogene autotemcel (exa-cel). Pivotal trials demonstrate that BCL11A disruption achieves sustained, pancellular fetal hemoglobin (HbF) reactivation, effectively eliminating vaso-occlusive crises (VOCs) in adolescents and adults. The recent 2026 U.S. Food and Drug Administration (FDA) expansion of exa-cel to children aged two years and older marks a critical inflection point, offering the potential to forestall irreversible organ injury, though it raises distinct ethical and toxicity concerns regarding myeloablative busulfan conditioning. Despite this transformative efficacy, the transition from proof-of-concept to a universally accessible cure confronts substantial barriers. We critically evaluate the ex vivo manufacturing bottlenecks—including stem cell mobilization attrition—and the stark global access disparities that currently constrain the reach of autologous gene therapy. Finally, we highlight future frontiers, including base and prime editing, non-genotoxic CD117-targeted conditioning, and in vivo lipid nanoparticle delivery, which are necessary to decouple molecular precision from logistical complexity and fulfill the promise of a globally accessible cure.