Md Mohiuddin, Md Al Mamun Ahsan
From a translational perspective, we argue that improvements in editing efficiency alone will be insufficient; clinical success will require the simultaneous achievement of tumor-selective delivery, genomic integrity, and acceptable long-term safety. Therefore, the continued development of novel approaches should be promoted to realize the full potential of CRISPR-Cas9 technology in oncology and other therapeutic applications.
BACKGROUND AND AIMS: CRISPR-Cas9 gene editing has transformed molecular biology and has great potential as a therapeutic tool for cancer and many other human diseases. This perspective review elaborates on the recent advances in CRISPR-Cas9 technology and its application as an innovative cancer treatment. Additionally, this perspective outlines the current barriers to clinical translation, including in vivo delivery and off-target effects, as well as potential mitigation strategies.
DISCUSSION: CRISPR-Cas9 has enabled the development of innovative methods to enhance immunotherapy, overcome drug resistance, and identify new therapeutic targets. Importantly, CRISPR-Cas9-induced DNA double-strand breaks can activate p53-mediated selection and cause unintended on-target genomic alterations, including large deletions, chromosomal rearrangements, and chromosome loss. While progress has been made toward addressing these significant obstacles, optimizing delivery systems, minimizing off-target effects, and addressing immunogenicity are critical for the successful clinical application of CRISPR-Cas9. Emerging strategies, including high-fidelity Cas9 variants, optimized guide RNAs, and advanced non-viral delivery systems such as lipid nanoparticles (LNPs) and exosomes, may improve the precision, safety, and delivery of CRISPR-Cas9-based therapies. Continued innovation in base editing and prime editing may enable the development of more refined approaches for precise genome modification.
CONCLUSION: From a translational perspective, we argue that improvements in editing efficiency alone will be insufficient; clinical success will require the simultaneous achievement of tumor-selective delivery, genomic integrity, and acceptable long-term safety. Therefore, the continued development of novel approaches should be promoted to realize the full potential of CRISPR-Cas9 technology in oncology and other therapeutic applications.