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CIRCLE-Seq for Interrogation of Off-Target Gene Editing
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Measurement and clinical interpretation of CRISPR off-targets

Ariella Angelini Stewart1, Rebecca C Ahrens-Nicklas2,3, Shengdar Q Tsai4

  • 1Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

Nature Genetics
|November 25, 2025
PubMed

Insights

CRISPR gene therapies offer new hope for diseases, but carry risks like off-target edits. This study presents a framework to assess CRISPR safety, moving therapies from lab to clinic.

Area of Science:

  • Genetics and Genomics
  • Biotechnology
  • Translational Medicine

Background:

  • CRISPR gene therapies are emerging as powerful tools in research and medicine.
  • These therapies hold promise for treating previously untreatable diseases.
  • However, genome-related adverse events, such as off-target edits, are inherent risks.

Purpose of the Study:

  • To address the inherent risks of off-target edits in CRISPR genetic therapies.
  • To propose a practical framework for evaluating and assessing off-target safety.
  • To facilitate the clinical translation of CRISPR therapeutics.

Main Methods:

  • Reviewing current understanding of off-target events in CRISPR technology.
  • Developing a framework for assessing the safety of CRISPR genetic therapies.
  • Considering both existing and future tools for safety evaluation.

Main Results:

  • The perception of near-zero off-targets for CRISPR therapies is unrealistic.
  • Not all genomic off-target events pose equal risks.
  • A practical framework for assessing off-target safety has been developed.

Conclusions:

  • A balanced assessment of therapeutic benefits and risks is crucial for CRISPR therapies.
  • The proposed framework aims to standardize off-target safety evaluation.
  • Streamlining the transition of CRISPR therapeutics from research to clinical application is the ultimate goal.

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