CRISPR protein shows promise in targeting cancer cells

Scientists are exploring a new cancer-fighting strategy that uses a programmable CRISPR enzyme to identify specific messenger RNA molecules produced by cancer cells and then shred the cells’ genomes, causing them to self-destruct.

The approach could provide a way to eliminate cancer cells that produce mutated proteins considered difficult to target with conventional drugs. Yang Liu, a molecular biologist at the University of Utah School of Medicine in Salt Lake City and co-author of one of the studies, described the system as a “molecular death switch” capable of recognizing a specific RNA sequence — essentially, a programmable form of chemotherapy.

A treatment based on the approach is already in the early stages of development at a biotechnology company in Zwingenberg, Germany, to target HPV-related head and neck cancers. Paul Schulze, a co-founder of the company and co-author of one of the studies, said the goal is to generate the first clinical-trial data by 2030.

A bacterial defense mechanism

CRISPR systems naturally occur in bacteria and other microorganisms, where they function as a form of immune defense. Some CRISPR systems use RNA molecules to guide CRISPR-associated enzymes toward DNA sequences in viruses and other invaders. The enzymes then cut the DNA, helping eliminate the threat.

For more than a decade, researchers have adapted such systems for genome editing by designing guide RNAs that direct the enzymes to specific genetic targets.

However, not all CRISPR enzymes work in the same way. Around a decade ago, Ryan Jackson, a biochemist at Utah State University in Logan, and his colleagues began investigating the mechanism of a protein known as Cas12a2.

The researchers initially assumed that the enzyme would behave similarly to other Cas proteins used in gene editing. Instead, repeated laboratory experiments failed to produce the expected results.

Eventually, Jackson’s team and another research group discovered that Cas12a2 operates differently. Once it recognizes RNA sequences matching its guide RNA, the enzyme becomes activated and begins cutting DNA indiscriminately, halting the growth of the infected cell.

In nature, this mechanism may help limit the spread of infection. “How did nature come up with such a trick?” asks René Bernards, a cancer geneticist at the Netherlands Cancer Institute in Amsterdam. “Whatever the answer, we can make very good use of it.”

A targeted cellular killer

Two research teams have now applied this mechanism to cancer. Both focused on tumors driven by mutated proteins that have proved difficult to target using conventional treatments.

One group programmed Cas12a2 to recognize RNA produced by cells carrying mutations in the TP53 gene, which is altered in roughly half of all cancers. The other targeted RNA produced from a mutated version of the KRAS gene, whose altered proteins can drive uncontrolled cell growth and are associated with some of the deadliest cancers.

In both studies, Cas12a2 demonstrated remarkable specificity. The enzyme selectively destroyed cells carrying cancer-associated mutations, even when the mutation differed from the normal RNA sequence by just a single nucleotide.

The approach worked in human cells grown in the laboratory and reduced tumors in living mice, including tumors driven by mutated TP53 or by HPV infection.

The technology remains far from being ready for use in patients, but the findings provide an important proof of concept for a potentially powerful therapeutic platform. Its applications could eventually extend beyond cancer to autoimmune and neurological diseases.

Safety and delivery challenges remain

Significant challenges must still be addressed. Cas12a2 must be delivered into target cells, a difficult task because the protein is relatively large. Further safety studies are also needed to ensure that the enzyme does not damage healthy cells.

So far, experiments have shown a high degree of selectivity, with Cas12a2 primarily destroying cells that produce the targeted mutant RNA. This could make the approach more selective than many conventional chemotherapy drugs, which can affect any rapidly dividing cells in the body.

Another concern is that the enzyme did not eliminate every cancer cell in the experiments, including cells grown in the laboratory. Researchers suggest that Cas12a2-based treatments could eventually be combined with other cancer therapies to improve their effectiveness and reduce the risk of tumors developing resistance.

Although Cas12a2-based therapies remain at an early stage, researchers say the technology has considerable room for improvement and could open a promising new path toward more precise cancer treatments.