The CRISPR Era and Beyond: Technical Milestones and Future Directions in Sickle Cell Disease Therapeutics

Abstract

Sickle cell disease (SCD) is a major hereditary blood disorder affecting approximately 8 million people worldwide, historically managed through symptomatic care and small-molecule disease-modifying agents. The pivotal 2023 FDA approvals of lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (Casgevy) marked a transformative shift toward potentially curative ex vivo genetic therapies. This review synthesizes key clinical trial data, regulatory filings, and translational literature to evaluate the trajectory of SCD therapeutics, spanning supportive management, small-molecule drugs, lentiviral gene addition, and CRISPR/Cas9 genome editing. In addition, this review examines the principal clinical, safety, manufacturing, economic, and ethical barriers impeding real-world translation. While these innovative cell therapies demonstrate remarkable clinical efficacy in reducing vaso-occlusive crises, their high financial costs, complex manufacturing logistics, and reliance on toxic myeloablative conditioning currently restrict widespread adoption. Consequently, although gene therapy offers unprecedented therapeutic potential, overcoming implementation bottlenecks and developing scalable, next-generation in vivo editing strategies will be essential to ensure these potentially curative breakthroughs become equitably accessible to the vast majority of affected individuals globally.