ON-Target Adverse Events of CRISPR-Cas9 Nuclease: More Chaotic than Expected

Area of Science:

• Genomics
• Molecular Biology
• Biotechnology

Background:

• CRISPR-Cas9 is a powerful gene editing tool with significant clinical potential.
• While off-target effects are understood, on-target genotoxicity remains a concern.
• Genomic alterations at the targeted locus can occur following CRISPR-Cas9 activity.

Purpose of the Study:

• To review the spectrum of genomic outcomes induced by CRISPR-Cas9 at the on-target locus.
• To highlight the underappreciated safety concern of on-target genotoxicity.
• To emphasize the need for better detection and prevention strategies for CRISPR-Cas9 clinical trials.

Main Methods:

• Literature review of studies investigating CRISPR-Cas9 induced genomic alterations.
• Analysis of reported on-target genotoxic events, including insertions, deletions, and large-scale rearrangements.
• Discussion of the implications for CRISPR-Cas9 safety and clinical translation.

Main Results:

• CRISPR-Cas9 can lead to a range of on-target genomic events, from small indels to megabase-scale rearrangements.
• These on-target genotoxic effects are complex and often difficult to detect.
• Current high-fidelity Cas9 variants primarily address off-target, not on-target, genotoxicity.

Conclusions:

• On-target genotoxicity is a critical, underestimated safety issue for CRISPR-Cas9 therapies.
• Understanding the mechanisms underlying these events is crucial for developing robust safety protocols.
• Further research and improved detection methods are essential for the safe clinical deployment of CRISPR-Cas9 technology.