A new review published in Genes & Diseases by authors from Cell and Gene Therapy Catapult and Guy's Hospital, United Kingdom, highlights the importance of non-clinical safety assessment in the development of CRISPR/Cas-modified cellular and gene therapy products, according to an Apr. 10 release.
As genome editing technologies such as CRISPR/Cas move from laboratory research to clinical use, ensuring patient safety through comprehensive non-clinical evaluation has become a central concern. The review provides a detailed examination of safety risks associated with both ex vivo and in vivo genome editing platforms.
The authors say that non-clinical programs must go beyond initial proof-of-concept studies to include analyses of toxicology, biodistribution, immunogenicity, tumorigenicity, and long-term persistence. They recommend that study designs be adapted to each product’s characteristics—such as delivery method, target tissue, and intended patient group—in line with regulatory guidance from agencies like the Food and Drug Administration (FDA) and European Medicines Agency (EMA).
Genotoxic risks are identified as a key issue due to double-strand DNA breaks induced by CRISPR. These breaks can lead to unintended genetic changes or responses that may increase cancer risk. The review notes recent advances—including high-fidelity Cas variants as well as base editing and prime editing techniques—that may help reduce these risks by minimizing off-target effects.
Delivery methods are also discussed in detail. While viral vectors can efficiently transfer genes but raise concerns about immune reactions or toxicity at higher doses, non-viral options such as lipid nanoparticles are emerging as safer alternatives because they allow only temporary expression of gene-editing proteins.
The review addresses additional challenges related to immune responses against Cas proteins derived from bacteria. Evidence suggests some people have pre-existing immunity against these proteins; therefore, strategies like immune screening or protein engineering may be necessary during clinical trials. The authors recommend integrating advanced guide RNA design tools and sequencing-based analysis for better detection of unintended effects.
Overall, the review concludes that multidisciplinary approaches for non-clinical safety evaluation will be crucial for moving genome-edited therapies into wider clinical use while maintaining strong patient protections.
