Mihaela Raluca Radu 1 #, Alina Prădatu 1 #, Dragos Cretoiu 1, 2 *, Catalina Micu 1
1 Materno-Fetal Medicine Excellence Center, Alessandrescu-Rusescu National Institute of Mother and Child Health, Bucharest, Romania
2 Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
# Authors have equal contribution
* Correspondence to: Dragos Cretoiu, Materno-Fetal Medicine Excellence Center, Alessandrescu-Rusescu National Institute of Mother and Child Health, Bucharest, Romania. E-mail: dragos@cretoiu.ro
Abstract
CRISPR-Cas9 genome editing, a Nobel Prize-winning technology discovered in 2012, has transitioned from labo-ratory tool to clinical therapy with the 2023–2024 approvals of exagamglogene autotemcel (Casgevy) for sickle cell disease (SCD) and transfusion-dependent β-thalassemia. These milestones represent the first regulatory endorse-ments of CRISPR-based treatments, addressing severe monogenic disorders by reactivating fetal hemoglobin. This review synthesizes translational lessons in clinical pharmacology, pharmacogenomics, and safety to inform broader applications in personalized medicine. Ex vivo CRISPR editing of autologous hematopoietic stem cells targeting the BCL11A enhancer achieves durable fetal hemoglobin induction (median >30% HbF), eliminating vaso-occlusive crises in ~97% of severe SCD patients over 12–24 months, with comparable success in β-thalassemia. Pharmaco-logically, edited cells exhibit engraftment kinetics similar to standard transplants, modulated by myeloablative con-ditioning. Pharmacogenomic factors, such as co-inherited α-thalassemia or HBG promoter variants, may influence response heterogeneity. Safety data show no off-target-related toxicities in trials (detection limit ~0.1% VAF), but preclinical evidence highlights risks of on-target structural variants (e.g., large deletions in 5–20% of edited cells) and potential clonal hematopoiesis. The first CRISPR approvals validate genome editing as a curative modality for hemoglobinopathies, demonstrating high short-term efficacy and acceptable safety, while underscoring needs for pharmacogenomic stratification and long-term surveillance.
