by Peter MacCallum Cancer Centre

Molecular principles of CRISPR-Cas13 mismatch intolerance enable selective silencing of point-mutated oncogenic RNA with single-base precision. Credit: Science Advances (2024). DOI: 10.1126/sciadv.adl0731

Peter Mac scientists have found a way to use the powerful gene editing tool CRISPR to silence cancer-causing gene mutations which, up to now, have remained off-limits to targeted drugs.

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Dr. Mohamed Fareh and colleagues have shown it is possible to silence the KRAS G12, NRAS G12D, and BRAF V600E gene mutations known to drive aggressive pancreatic, colorectal and lung cancers.

Their novel method was able to selectively degrade RNA messages from these mutant genes while having no effect on related healthy genes. A paper describing this approach has just been published in Science Advances.

“This work demonstrates the incredible potential of CRISPR-Cas13 to act as a precise, mutation-specific drug,” says Dr. Fareh, who led this work along with Dr. Carolyn Shembrey at Peter Mac.

“With further development, this platform could transform the way we treat cancers driven by hard-to-target mutations.

“The precision and adaptability of this system also opens new doors to personalized cancer treatments tailored to an individual’s unique genetic profile.”

CRISPR is a powerful tool that scientists use to target and disable or edit specific DNA in cells. Cas13 is a protein involved in this process which enables this tool to target RNA—the downstream information sent by DNA—rather than DNA itself.

The mutations that were successfully silenced are single-nucleotide variants (SNVs), which are small changes in the genetic code that fuel uncontrolled cell growth.

“These SNVs have been notoriously difficult to target with traditional drugs,” says Dr. Fareh.

“By introducing strategic mismatches in the CRISPR guide RNA, we successfully reprogrammed CRISPR-Cas13 to selectively degrade mutant RNA transcripts while sparing the normal, unmutated versions expressed in healthy cells.”

Dr. Farah explained this approach not only overcomes the limitations of earlier therapeutic applications of CRISPR but also achieves one of the most important features of true, targeted drugs—it blocks only the mutated forms of the genes.

“This provides significant promise for greater efficacy and diminished side-effects,” he said.

This method can silence these SNVs with an unprecedented level of accuracy and flexibility; however, this has been demonstrated in a lab setting and more work is needed before this novel method can be tested in people.

This research was led by first author Dr. Shembrey under the co-supervision of Dr. Fareh along with Associate Professor Paul Ekert and Professor Joe Trapani.

More information: Carolyn Shembrey et al, Principles of CRISPR-Cas13 mismatch intolerance enable selective silencing of point-mutated oncogenic RNA with single-base precision, Science Advances (2024). DOI: 10.1126/sciadv.adl0731

Journal information:Science Advances

Provided by Peter MacCallum Cancer Centre

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