Selective CRISPR enzyme kills cancer cells by shredding their DNA

Good news! Cancer is history (soon)!

"A peculiar type of CRISPR enzyme that slashes DNA into pieces has been used to control cancer in mice.

The enzyme, called Cas12a2, can be engineered to recognize a particular RNA sequence. When it finds its target, the enzyme goes wild, indiscriminately cutting up DNA.

Two separate research teams have used the CRISPR enzyme to target RNA made by cancer cells with mutated TP53 or KRAS genes. The treatment killed a proportion of lab-grown cancer cells and shrank tumours in mice. 

“There’s obviously still room to improve it,” ..."

"... A therapy that uses this approach to target head and neck cancers caused by human papillomavirus (HPV) is already in early development at Akribion Therapeutics, a biotechnology company in Zwingenberg, Germany. ..."

"... The research team engineered a CRISPR system called CRISPR-Cas12a2 to look for the specific RNA transcript produced only by cells with the mutated cancer gene.

In bacteria, this CRISPR acts as a suicide pill, intentionally killing a cell that has been infected by a virus to prevent its spread.

In the newly engineered version, once the system detects a cancer signature within a cell, the Cas12a2 enzyme activates and initiates “chromatin shredding,” slicing up all the genetic material inside that specific cell. This widespread genetic demolition triggers cell death, destroying mutated cells while leaving healthy cells completely untouched. ..."

From the abstract (1):

"Genetic mutations that drive cancer often occur in tumour-suppressor proteins such as the p53 transcription factor, which is altered in 40–50% of cases.

However, current therapies often fail to target these mutations because the mutant proteins typically lack defined drug-binding pockets and restoring their endogenous function has proven challenging.

Here we program Cas12a2, an RNA-guided CRISPR nuclease with trans-nucleolytic cleavage activity, to kill cancer cells selectively by targeting cancer-specific transcripts.

This approach limited cell growth by inducing trans shredding of chromatin and triggering DNA-damage responses and cell death.

In contrast to existing methods, RNA-guided Cas12a2 senses cellular RNA signatures, enabling precise targeting of undruggable mutations.

Transcript-activated chromatin shredding provides an innovative approach to precision disease treatments for undruggable targets."

From the abstract (2):

"Selectively eradicating target cells on the basis of their genetic or transcriptional identity remains important in basic research, medicine, biotechnology and agriculture.

For applications involving bacteria, CRISPR nucleases offer promising options due to their ability to enact RNA-guided counterselection; however, using these same nucleases for counterselection in eukaryotes has proven much more restrictive.

Here we show that Cas12a2, a recently discovered type V CRISPR nuclease, exhibits RNA-triggered DNA shredding, and enables programmable and sequence-specific elimination of yeast and human cells expressing a target transcript.

Triggering Cas12a2 elicits rampant double-stranded DNA breaks in trans, leading to cell death.

Cell killing can be activated by a wide range of target transcripts, with no observed off-target activation.

Leveraging this approach, we selectively eliminate cells that harbour human papillomavirus, cells that failed to undergo gene editing, or cells that encode a prevalent oncogenic point mutation in KRAS.

These findings expand the CRISPR toolbox to allow the selective elimination of eukaryotic cells on the basis of their transcriptional profile."

Nature Briefing: Cancer 

Bizarre CRISPR enzyme kills cancer cells by shredding their DNA "Early tests suggest the protein can be aimed at targets with tumour-causing mutations."

New CRISPR Technique Selectively Shreds Cancer Cells, Including “Undruggable” Cancers (original news release) "Innovative chromatin shredding technique shown to selectively destroy cancer cells carrying a mutation found in nearly half of all cancer cases"

Targeting cancer-specific mutations with RNA-triggered chromatin shredding (1; no public access, senior author is Jennifer A. Doudna, Nobel Prize winner in chemistry for CRISPR-Cas)

Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding (preprint of 1, open access, but preprint was apparently not updated to match the journal article)

RNA-triggered cell killing with CRISPR–Cas12a2 (2; open access)

Fig 2 Cas12a2 induces acute DNA damage and cell cycle arrest upon RNA targeting in mammalian cells.

Fig. 3: Cas12a2 has limited off-target activation in human cells.