CRISPR-Cas9 gene editing in sickle cell disease shows high efficacy in preventing vaso-occlusive crises

Study Design and Population: This phase 3, single-group, open-label randomized clinical trial investigated the efficacy of exagamglogene autotemcel (exa-cel), a nonviral CRISPR-Cas9 gene-edited therapy, in patients aged 12 to 35 years with severe sickle cell disease. The study included patients who experienced at least two severe vaso-occlusive crises annually in the two years prior to screening. The therapeutic intervention involved editing CD34+ hematopoietic stem and progenitor cells (HSPCs) and administering a myeloablative conditioning regimen with busulfan.

Main Findings: Of the 44 participants treated, 30 with sufficient follow-up demonstrated a significant response. Ninety-seven percent (29 of 30) remained free from severe vaso-occlusive crises for at least 12 consecutive months, and 100% (30 of 30) avoided hospitalization for these crises over the same period. The intervention showed a high safety profile, consistent with myeloablative busulfan conditioning and autologous HSPC transplantation, with no cancers reported during the follow-up.

Implications for Practice: The results suggest that exa-cel can effectively eliminate severe vaso-occlusive crises in patients with sickle cell disease, marking a substantial advance in treatment options. These findings may pave the way for broader application of gene-editing therapies in hematologic diseases, pending further research on long-term outcomes and safety.

Reference: Frangoul, H. et al. (2024). Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med, Online ahead of print. DOI: 10.1056/NEJMoa2309676.