CRISPR/Cas12a2 selectively destroys diseased human cells

A new CRISPR-based approach has been designed to selectively eliminate human cells with disease-causing genes in vitro.

Researchers in the USA and Germany have adapted a bacterial immune system to target and kill cancerous and virus-infected human cells grown in the laboratory. The approach relies on Cas12a2, a bacterial enzyme that can 'shred' genetic information (see BioNews 1175) and can be directed to be activated by a genetic (RNA) sequence only carried by certain cells.

'Because Cas12a2 can be programmed with a guide RNA to target any RNA sequence, and it shows little to no off targeting, we believe we have discovered a way to selectively kill cells across all of biology,' said Dr Ryan Jackson at Utah State University, a senior author on the study published in Nature. 'We show it can be used to enrich for gene editing, and to selectively kill cells harbouring virus genes, and to kill cells with acquired mutations.'

CRISPR/Cas9 approaches are more commonly associated with genome editing, where a guide RNA directs the Cas9 protein to make precise changes in a specific sequence. In this new approach, the Cas12a2 protein is also guided by a guide RNA but, once activated by its target, Cas12a2 kills the cell by indiscriminately cutting through genetic material. The authors previously worked with Cas12a2 in bacteria, while this new study applies this system in yeast and human cells.  

A challenge in therapeutics is to target diseased cells without damaging healthy ones. Recognition of a viral-specific gene or cancer-associated mutation can distinguish these cells genetically, and the Cas12a2 protein provides a general mechanism to eliminate the diseased cells. In this study, the target genes are often artificially highly expressed to clearly distinguish the cells, but cancer and viral genes are also often highly expressed in disease.  

'The enzyme that we're working with is extremely specific,' said Dr Yang Liu from the University of Utah, a corresponding author on the study. 'It does not touch the healthy cells. So, if we're thinking about a cancer therapy, you're treating cancer with no side effects.'

Previous work showed that Cas12a2 could slow the growth of human papillomavirus-associated tumours in mice. A new study from the same authors, which is yet to be peer-reviewed, extends these results to a gene mutated in about half of all cancers. However, further work is required to establish the safety and efficacy of Cas12a2 in animal models before this approach can be used in human clinical treatments.