Ten years of clinical genetic therapies for sickle cell disease: Current and future directions

Gene therapy for sickle cell disease (SCD) has advanced rapidly over the past decade, beginning with the first clinical trial 10 years ago and culminating in FDA approval of ex vivo lentiviral and CRISPR-based therapies in 2023. Investment and scientific interest remain high, with both academia and industry actively pursuing next-generation strategies. The field is also shaped by complex economic realities, the discontinuation of otherwise promising programs, and the shifting role of academia as industry pivots toward in vivo platforms. Emerging in vivo gene therapies offer the potential to simplify delivery, reduce conditioning toxicity, and expand global accessibility, but remain preclinical or early-stage, leaving patients and clinicians to navigate difficult trade-offs between current ex vivo options and waiting on experimental in vivo therapies. Manufacturing, mobilization, and long-term durability continue to pose practical and clinical challenges, while real-world outcomes remain largely unmeasured outside clinical trials. This review synthesizes recent developments in ex vivo and in vivo gene therapy for SCD, highlighting the scientific, regulatory, and economic forces shaping the field. Ongoing challenges, future directions, and the critical importance of long-term follow-up and real-world registries are discussed. By providing a contemporary snapshot, the review contextualizes therapeutic progress, clarifies the trajectory of research, and illuminates how patients are affected by the rapid evolution of gene therapy for individuals with SCD.