A method for altering RNA that works similarly to the CRISPR DNA-editing technique has proven effective in animal tests and could be a powerful new tool for doctors.

The approach, created by a team led by Prashant Mali at the University of California, San Diego, is inherently safer than CRISPR because it doesn’t alter the genome. What’s more, it could be used to temporarily alter gene expression, which could treat conditions such as chronic pain.

“This is a clever and elegant approach,” says Gaetan Burgio at the Australian National University in Canberra. “Overall, I believe this technique has great potential.”

The recipes for making the proteins our bodies require are stored in the DNA inside cells. When we need proteins, our cells use DNA to create a version in the form of RNA, which is single-stranded. This “messenger RNA”, or mRNA, is then sent to the cell’s protein-making factories.

But mRNA strands aren’t simple copies of the recipes, or genes. They can get changed in many ways before being used as protein templates. Cells have complex RNA-editing systems, which do everything from cutting out the junk in our genes that gets transferred to RNA, to changing the sequence itself.

Read more: Bacterial RNA-editing tool could disable viruses or halt disease

Sometimes, two parts of a single RNA piece can bind to form a double strand. When this happens, so-called ADAR enzymes in our cells recognise the double-stranded section and edit the sequence by effectively changing the letter A in the RNA code to a G at specific sites. Exactly why is unknown.

These bits of double-stranded RNA can be created artificially by adding “antisense RNA”, which are pieces of RNA whose sequence is complementary to part of a strand of mRNA. This method has been used before to edit RNA, but it doesn’t work very well, perhaps because antisense RNA rapidly breaks down.

Now, Mali and his colleagues have tried using circular pieces of antisense RNA, which are more stable. This boosted the percentage of mRNA with the desired edit around fourfold, to as high as 90 per cent in human cells in a dish. The effect also lasted much longer, for several days.

Next, the team used the approach to treat mice with the same mutation that causes Hurler syndrome in people. This mutation disables an enzyme, leading to a build-up of harmful sugars. Mali’s team managed to correct up to 20 per cent of the mutant RNA in the mice’s livers, halving the sugar build-up.

For this experiment, a virus was used to deliver DNA coding for the antisense RNA to the cells. Although the DNA wasn’t integrated into the genome, this means the effect lasts indefinitely. But antisense RNAs could also be delivered in fatty droplets, as is done in some of the new covid-19 mRNA vaccines, in which case the effects would last only weeks.

This approach is limited to changing A to a G in the RNA code. But it might be possible to develop similar approaches that would enable a C to U change.

Journal reference: bioRxiv, DOI: 10.1101/2021.01.12.426286v1