Genotoxic safety and long-term engraftment dynamics of efficient translational CRISPR/Cas9 therapeutics for β-haemoglobinopathies from bench to clinical trials

CRISPR/Cas9-mediated gene editing targeting the BCL11A erythroid enhancer has transformed therapeutic approaches for transfusion-dependent β-thalassemia (β-thal) and sickle cell disease (SCD). Even though clinical efficacy is well demonstrated, translating these therapies to global patient populations requires a strong evidence-based framework to address critical concerns regarding long-term genotoxic safety and long-lasting engraftment dynamics. Following the 2020 PRISMA guidelines, we conducted a systematic review of 21 key clinical and preclinical studies (published during 2014–2026) to evaluate CRISPR/Cas9-mediated gene editing in β-thal and SCD. The inclusion criteria focused on studies reporting foetal haemoglobin (HbF) induction, transfusion independence (TI) and safety outcomes. Clinical data indicate high efficacy, with exagamglogene autotemcel (exa-cel) achieving TI in 91% of β-thal patients and a vaso-occlusive crisis (VOC)-free status in 97% of SCD patients. Safety profiling confirmed that severe adverse events, including febrile neutropenia and stomatitis, are primarily associated with busulfan-based myeloablation rather than gene editing. Gene-editing safety and conditioning toxicity are interlinked because conditioning is part of the process, and edited clones might interact with stress pathways during long-term repopulation. Preclinical benchmarks substantiate molecular reliability, with negligible off-target activity reported in most validated platforms. However, rare instances of complex structural rearrangements and intergenic off-target indels highlight the necessity for in-depth, unbiased long-term genomic surveillance. CRISPR/Cas9 therapeutics for β-thal and SCD treatment constitute a treatment option within current clinical frameworks. These therapies need continuous surveillance. Rather than establishing a perfect plan, this systematic review highlights that while current platforms are thought to have short-term molecular precision, the use of Multilayer Safety Risks Screening and Surveillance for pretransplant conditioning is critical. This approach helps address long-term genotoxic concerns and ensures the safety and scalability of gene-editing therapies for global β-thal and SCD patient care.