From Bench to Bedside: Multidimensional Clinical Applications and Challenges of CRISPR Genome Editing

Abstract

CRISPR-Cas9 gene editing has shifted from the laboratory to clinical application in specific diseases, where, in β-hemoglobinopathies, disrupting the BCL11A erythroid enhancer can reactivate fetal hemoglobin, functionally curing transfusion-dependent β-thalassemia and sickle cell disease, ultimately giving birth to Casgevy™, the first approved CRISPR therapy. In oncology field, CRISPR-engineered T cells precisely insert CARs into TRAC locus or knock out immune checkpoints such as PD-1, thereby showing enhanced persistence, reduced exhaustion and high response rates in hematologic malignancies such as multiple myeloma, while in solid tumors, α-thalassemia due to large fragment deletions of HBA1/HBA2, hemophilia A limited by F8 cDNA size exceeding viral packaging capacity and acute respiratory viral infections such as SARS-CoV-2 and influenza, significant obstacles still exist. These challenges include inefficient delivery, lack of physiological bypass mechanisms, rapid viral mutation, and a narrow therapeutic window; furthermore, Casgevy™’s cost of up to 2.2 million dollars highlights a critical accessibility gap, with use limited to affluent healthcare systems. Emerging solutions include double-strand break-free base editors and prime editors, in vivo delivery via lipid nanoparticles, and multimodal therapeutic regimens; however, without synchronous progress in equitable pricing and global accessibility, CRISPR’s curative potential will remain unrealized for the majority of patients worldwide.