Paper of the field n°10
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Abstract for General public
Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases that significantly impair health-related quality of life. Exagamglogene Autotemcel (exa-cel), also known as Casgevy, is a cellular therapy approved for the treatment of TDT and SCD. It is characterised by CRISPR-Cas9 gene-editing in hematopoietic stem and progenitor cells (HSPCs) targeting the erythroid-specific enhancer region of BCL11A to reactivate the production of foetal haemoglobin (HbF) in patients. Early study demonstrated >80% of BCL11A editing in HSPCs, resulting in robust reactivation of HbF. These effects remained stable in subsequent advanced studies, in which patients treated with a single-dose consistently maintained high levels of BCL11A editing (60-80%) and sustained HbF reactivation (~30%). Therefore, the severe clinical manifestations, such as vaso-occlusive crisis, were markedly reduced or eliminated for 12 months or longer.
While initial safety study showed no evidence of editing at unwanted sites, known as off-targets, more sensitive analysis revealed one potential off-target site within an intron of the CPS1 gene, located on the same chromosome as BCL11A. Notably, this off-target effect occurred only in the presence of a specific CPS1 genetic variant, as shown by comparative analysis of HSPCs from donors with and without this specific variant. As a consequence, patients participating in the advanced studies were prospectively screened for the presence of the specific CPS1 variant as well as other variants that could predispose to potential off-targets. Yet, no editing was observed and in individuals carrying the CPS1 variant, only minimal editing was observed. After 40 months of follow-up, these patients showed no treatment-related adverse effects and maintained sustained clinical benefit. Importantly, CPS1 has no known or hypothesised role in hematologic cancers, and is neither expressed in, nor has functionally associated with blood cells. Taking all together, Casgevy shows a favourable efficacy and safety profile for the treatment of patients aged 12 or older with TDT and SCD. The treatment is so far associated with substantial improvements in physical, emotional, social functioning well-being and pain experience, resulting in a clinically meaningful enhancement of overall quality of life.
For more information see Casgevy | European Medicines Agency (EMA).
Abstract written by Melissa Whitehead from Universitätsklinikum Freiburg (Germany)
Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. The New England Journal of Medicine, 2020. DOI: 10.1056/NEJMoa2031054
Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. The New England Journal of Medicine, Vol 390, No 18, May 2024.
Yen A, Boitano T, Zappala Z, et al. Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel – Update. The New England Journal of Medicine, Oct 2025. DOI: 10.1056/NEJMc2503294
Sharma A, Locatelli F, Bhatia M, et al. Improvements in health-related quality of life in patients with severe sickle cell disease after exagamglogene autotemcel. Blood advances, vol 9, no 24, Dec 2025.
