A one-off injection might permanently reduce the risk of heart disease by reversibly switching off a gene in the liver, according to a study in mice. The findings suggest that the approach used, called epigenome editing, can produce long-term changes in gene activity without the potential risks associated with permanent gene editing.
Liver cells produce a protein called PCSK9 that breaks down another protein that removes cholesterol from the blood. So blocking the PCSK9 protein, or stopping it being made, can lower cholesterol levels and should cut the risk of heart disease.
There are already cholesterol-lowering drugs that work in this way, but they require injections every few weeks because they can’t be taken in pill form.
One alternative is to permanently disable the PCSK9 gene in liver cells by editing its DNA sequence. In May, biotech firm Verve Therapeutics got the go-ahead in New Zealand to trial this in people with an inherited genetic condition that causes dangerous cholesterol levels.
But such techniques can theoretically result in unwanted DNA changes, which could turn cells cancerous, although there are no reports of this happening in any gene-editing trials so far. For people with serious inherited conditions, that risk might be acceptable, but for wider use, epigenome editing could be preferable.
Instead of cutting DNA strands and altering their sequence, epigenome editing tools add or remove chemical tags that control gene activity. Because of this, there should be no risk of them causing potentially dangerous mutations.
It should be possible to reverse epigenomic changes if there are undesirable effects
Angelo Lombardo at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, and his colleagues have now delivered an epigenetic tool for shutting down the PCSK9 gene in cells to the livers of mice. It is in the form of messenger RNA molecules, which encode a protein to edit the epigenome. Cholesterol levels in the mice were halved, and Lombardo thinks it will be possible to cut them more. “I’m sure there are ways to improve the efficacy,” he says.
What’s more, the researchers tested the mice at various times over 220 days and the effect lasted as long as they kept testing, suggesting it is permanent.
Other teams have only managed to create such a lasting effect by getting cells to continuously produce epigenome editors. Lombardo says his team’s editor was only produced for a few days and would have then broken down and disappeared. The team presented the work at a meeting of the American Society of Gene & Cell Therapy last month.
In theory, it should be possible to reverse epigenomic changes and switch genes back on if there are any undesirable effects, says Lombardo.
The results are good, says Luca Magnani at Imperial College London. But epigenome editing isn’t yet ready for testing in people, he says.
