Application and Breakthrough of CRISPR-Cas9 Gene Editing Technology in the Clinical Treatment of Sickle Cell Disease

Abstract

S i c k l e C e l l D i s e a s e ( S C D ) i s a n i n h e r i t e d hemoglobinopathy caused by a point mutation (GAG→GTG) at the 6th codon of the β-globin gene (HBB). Among traditional treatments, hydroxyurea requires lifelong administration and some patients show poor response; although hematopoietic stem cell transplantation (HSCT) can cure the disease, only 18% of patients can find HLA-matched donors, and there is also the risk of graft-versus-host disease (GVHD). The CRISPR-Cas9 gene editing technology provides a potential curative option for SCD by precisely modifying hematopoietic stem/progenitor cells (HSPCs). This article systematically reviews the clinical application strategies, experimental evidence, and existing challenges of this technology, and discusses its translational prospects in combination with the latest research findings. It covers the clinical effects of strategies such as targeting the BCL11A gene enhancer to activate fetal hemoglobin (HbF), directly correcting the E6V mutation of the HBB gene via homology-directed repair (HDR), and mimicking hereditary persistence of fetal hemoglobin (HPFH), as well as safety and accessibility challenges (e.g., off-target effects, preconditioning toxicity, and high treatment costs) and their corresponding solutions, aiming to provide comprehensive references for the research and application of gene therapy in SCD.