Measurement and clinical interpretation of CRISPR off-targets.
Publication Year:
2025
PubMed ID:
41286106
Public Summary:
We are a group of physicians and scientists developing CRISRP gene therapies. In this perspective, we outline how we are approaching the challenge of unintended changes to the genome that can result from CRISPR editing (genomic off-targets). We create a framework for interpreting off-targets scientifically and clinically.
Scientific Abstract:
CRISPR genetic therapies are revolutionizing the landscape of preclinical research and clinical studies, providing new potential routes for curative intervention for a range of previously untreatable diseases. As with any therapy, the therapeutic benefits and risks must be weighed against consideration of the disease threat. Genome-related adverse events are an inherent risk of CRISPR genetic therapies, including off-target edits. The perception that CRISPR therapies ought to have near-zero off-targets belies clinical medicine, therapy development and biology, which demonstrate that 'perfect' therapeutics do not exist. Given that not all genomic off-target events are equal, we provide a practical framework to evaluate and assess off-target safety based on the tools available today and ones that will be developed in the future. With the comprehensive information and assessment gathered using these guidelines, we aim to streamline the transition of CRISPR therapeutics from bench to bedside.
