The hidden risks of CRISPR/Cas: structural variations and genome integrity

Area of Science:

• Genomics
• Molecular Biology
• Gene Editing Technologies

Background:

• CRISPR/Cas technology offers revolutionary genome engineering capabilities with significant therapeutic potential.
• While off-target mutations are a known concern, large structural variations (SVs) like chromosomal translocations and deletions are emerging as critical safety issues.
• These SVs are particularly noted in cells treated with DNA-PKcs inhibitors, posing risks for clinical applications.

Purpose of the Study:

• To review the emerging evidence on CRISPR-induced on-target aberrations and chromosomal translocations.
• To identify knowledge gaps regarding the DNA repair pathways involved in these adverse events.
• To discuss strategies for enhancing the safety of genome editing technologies.

Main Methods:

• Literature review of recent studies on CRISPR/Cas-associated genomic alterations.
• Analysis of findings related to large structural variations (SVs) and their association with specific inhibitors.
• Synthesis of information on DNA repair mechanisms and their role in genome editing outcomes.

Main Results:

• CRISPR/Cas editing, especially with DNA-PKcs inhibitors, can induce significant on-target large structural variations (SVs), including translocations and large deletions.
• These SVs represent a substantial safety concern that has been previously undervalued.
• Current understanding of the underlying DNA repair pathways contributing to these SVs is incomplete.

Conclusions:

• The generation of large structural variations is a critical safety consideration for CRISPR-based therapies.
• Further research into DNA repair pathways is necessary to understand and mitigate these risks.
• Developing strategies to improve the safety profile of CRISPR genome editing is essential for clinical translation.