A CRISPR gene editing protein called Cas12a2 can be turned into a kind of programmable self‑destruct switch for cells, which researchers think could be a new way to treat conditions like cancer if the technique is validated.
Cas12a2 eliminates eukaryotic cells based purely on which RNA transcripts they express, and the investigators showed this can be used to selectively destroy virus‑infected cells, unedited cells, and cancer cells bearing a single‑nucleotide mutation.
“Common molecular and cell-based interventions, such as small-molecule inhibitors, toxins, antibodies, lytic viruses or programmed immune cells, eliminate cells through specific proteins or survival pathways; however, these methods cannot be tailored to arbitrary genetic or transcriptional states as well as difficult-to-drug scenarios such as mutations in non-coding sequences or complex etiologies,” write co-lead author Yang Liu, PhD, assistant professor in biochemistry at University of Utah Health, and colleagues in Nature.
“A cell-killing approach triggered directly by the specific recognition of prescribed DNA or RNA sequences could greatly broaden the range of targetable conditions, creating new means to counter select against specific cells in a variety of situations and applications.”
In this study, the researchers first tested the technology in yeast and human cell lines against a harmless target. They found that the guided Cas12a2 destroyed the cells carrying the marker by effectively shredding their DNA. When they checked for off-target effects they were rare and weak.
They then tested the technology on cancer cells carrying the HPV virus by targeting viral RNA. The method killed cells containing the virus, but not cells negative for HPV. The team also used the Cas12a2 method to “clean up” after gene editing by killing unedited cells and enriching edited ones. Finally, they tested if Cas12a2 could recognize a single mutation in the cancer gene KRAS and showed it could destroy cells with this mutation while leaving cells with a non-mutant version of KRAS alone. This worked even when those cells were resistant to an approved KRAS drug.
“The enzyme that we’re working with is extremely specific,” Liu says. “It does not touch the healthy cells. So if we’re thinking about a cancer therapy, you’re treating cancer with no side effects. That was striking to us. We did not know that was possible.”
This research is early stage, and it will take some time to enter the clinic, as testing in animal models is needed first, but the research team say the results are promising. The technology is being developed commercially by German biotech Akribion Therapeutics, a biotech spin-off from BRAIN Biotech launched in 2024.
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