A one-off injection might be able to 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. This means that blocking the PCSK9 protein, or preventing it being made, can lower cholesterol levels and should thus reduce the risk of heart disease.
There are already cholesterol-lowering drugs that work in this way, but they have a disadvantage 鈥� they all require regular injections every few weeks, because the drugs cannot be taken in pill form.
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One alternative is to permanently disable the PCSK9 gene in liver cells by altering its DNA sequence using gene editing. In May, a company called Verve Therapeutics got this approach in people with an inherited genetic condition that causes dangerously high cholesterol levels.
Verve is using a technique called base editing. Studies by other groups show that base editing can produce , which in theory 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 might be preferable.
Instead of cutting DNA strands and altering their sequence, epigenome editing tools merely add or remove chemical tags that control gene activity. Because of this, there should be no risk of them causing potentially dangerous mutations.
at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, and his colleagues have now developed several different epigenetic tools for shutting down the PCSK9 gene and have tested them in cells. They delivered the most effective one to the livers of mice 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 reduce them even further
鈥淚鈥檓 sure there are ways to improve the efficacy,鈥� he says.
What鈥檚 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 essentially permanent. This is a big step forward because achieving this kind of long-term effect has proved difficult.
Other teams have only managed this by getting cells to continuously produce epigenome editors. By contrast, Lombardo says his team鈥檚 epigenome editor was only produced for a few days and would have then broken down and disappeared. The team presented the work at a of the American Society of Gene & Cell Therapy last month.
In theory, it should also be possible to reverse epigenomic changes and switch genes back on if there are any undesirable effects, says Lombardo, although his team hasn鈥檛 tried to do this.
The results are good, says at Imperial College London. But epigenome editing isn鈥檛 yet ready for testing in people, he thinks. 鈥淲e are still far from direct intervention in humans,鈥� he says.
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