Researchers have uncovered that a molecule used to increase the efficiency of CRISPR-Cas9 gene editing destroys parts of the genome. 

The team discovered that while AZD 7648 does improve efficiency, it has the unwanted side effect of destroying other areas of the genome. They argue that alternatives should be found. 

CRISPR-Cas9 activates two natural repair mechanisms. The slow variant is called homology-directed repair and allows the precise integration of individual DNA segments into a desired gene region. 

AZD7648 forces the cell to use homology-directed repair and was expected to accelerate the development of more efficient gene therapies. The molecule is also currently in clinical trials as a potential cancer treatment.  

A research group led by Jacob Corn, Professor of Genome Biology at ETH Zürich, has discovered that the use of AZD7648 has led to massive genetic changes and the deletion of thousands of DNA bases. 

“When we analysed the genome at the sites where it had been edited, it looked correct and precise. But when we analysed the genome more broadly, we saw massive genetic changes. These are not seen when you only analyse the short, edited section and its immediate neighbourhood,” said Grégoire Cullot, a postdoctoral fellow in Corn’s group and first author of the study. 

The scientists suspect that they do not yet have a complete picture of the full extent of the damage because they did not look at the entire genome when analysing the modified cells, only partial regions. 

Corn commented: “For us, this is a major setback because, like other scientists, we had hoped to use the new technique to accelerate the development of gene therapies.” However, he adds: “The development of any new technology is a rocky road. One stumble does not mean we give up on the technology.”

Diana Spencer, Senior Digital Content Editor, DDW