ESMO TAT 2023 | Limitations and solutions associated with CRISPR technology

Eliana Ruggiero, PhD, San Raffaele Scientific Institute, Milan, Italy, comments on the technical limitations associated with the use of CRISPR technology, but also on the solutions arising to meet these challenges. Firstly, unplanned off-target gene disruption is a current limitation of the technology, but solutions such as prediction tools to assist in identifying possible off-target genes, the use of more advanced CRISPR-associated (Cas) nucleases, and the development of Cas9 nucleases that are catalytically inactivated, are all being employed. Possible immunogenicity, given the presence of antibodies against Cas9 in our circulation, also poses a safety risk in immunotherapy trials. However, multiplex gene-editing of T-cells has been observed in a previous study to trigger no such immune response in patients. Further limitations in the efficiency of Cas component delivery also arise, though Cas9 nucleases continue to undergo improvement and the possibility of direct base editing arises to mitigate this. Lastly, challenges of genotoxicity arising during Cas component delivery may be overcome using specific viral vectors that do not integrate, or by employing lipid nanoparticles as delivery mechanisms which are low cost and highly compatible. This interview took place at the ESMO Targeted Anticancer Therapies (TAT) Congress 2023 in Paris, France.

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