A one-off injection could one day lower your cholesterol levels for the rest of your life (New Scientist, 2017).

People born with natural mutations which disable a specific gene have a lower risk of heart disease, with no apparent side effects. Now a single injection has successfully disabled this gene in animal tests for the first time. This potential treatment would involve permanently altering the DNA inside some of the cells of a person’s body, so doctors will have to be sure it is safe before trying it in people. But the benefits could be enormous. In theory, it could help millions live longer and healthier lives.

The results of the animal study were described by Lorenz Mayr, of AstraZeneca, at a genomics meeting in London on February 1st. Lorenz Mayr, who leads AstraZeneca’s research into CRISPR, wouldn’t say whether the company plans to pursue this approach, but he was clearly excited as he presented the findings. He said “The idea would be to do it as a one-off. It should be permanent.”

Heart attacks and strokes kill a quarter of people living in rich nations, and high levels of “bad” LDL cholesterol in the blood greatly increases the risk. For this reason, millions of people now take statins to lower their LDL cholesterol levels. While statins undoubtedly extend the lives of many people, some experience side effects such as muscle pain, leading drug companies to look for alternative treatments. In 2005, it was discovered that a few people naturally have very low cholesterol levels, thanks to mutations that prevent their livers from making a protein called PCSK9. “They have a lower incidence of cardiovascular disease and no apparent side effects whatsoever,” said Gilles Lambert at the University of Reunion Island, who studies PCSK9.

The PCSK9 protein normally circulates in the blood, where it degrades a protein found on the surface of blood vessels. This second protein removes LDL cholesterol from the blood: the faster it is degraded by PCSK9, the higher a person’s cholesterol levels. But people who lack PCSK9 due to genetic mutations have more of this LDL-removal protein, and therefore less cholesterol in their blood. To mimic this effect, two companies have developed approved antibodies that remove the PCSK9 protein from the blood. Giles Lambert said these are very effective at lowering cholesterol and no serious side effects have been reported so far. It is yet to be shown if they reduce the risk of cardiovascular disease, but the first trial results are due to be announced in March.

However antibody drugs are extremely expensive and need to be injected every two to four weeks, so even if the antibodies work as well as hoped, they cannot be dished out to millions like statins. All attempts to develop conventional drugs to block PCSK9 have failed. But gene editing provides a radical alternative. Using CRISPR, the team at AstraZeneca have disabled human versions of the PCSK9 gene in mice. They did this by injecting CRISPR Cas 9 protein and a guiding RNA sequence into the animals. The RNA guide helps the Cas9 protein bind to a specific site in the gene. It then cuts the gene at that point, and when the break is repaired, errors that disable the gene are likely to be introduced.

There was an even bigger fall in cholesterol levels in the mice given the CRISPR treatment than in those injected with the antibody drugs. This gene editing approach would be a closer mimic of what happens in people born with PCSK9-disabling mutations than injecting antibodies, said pharmacologist Patricia McGettigan of Queen Mary University of London, who has looked at the safety of PCSK9 therapies. She said “That might actually be really productive.”

The big worry about using gene editing to alter DNA inside the body is that it could also cause unintended “off-target” mutations. In the worst case, these could turn cells cancerous. Lorenz Mayr said the team has tested for off-target effects in twenty six different tissues in the mice, and that the results will be published soon. He said “It’s very promising in terms of safety.”

CRISPR is constantly being improved. Other teams have developed modified versions of the CRISPR protein that are so precise off-target effects occur no more often than natural mutations in cells. Even so, Giles Lambert thinks human trials are at least a decade away. He said “For now it’s very far-fetched.”

An alternative approach that should have fewer off-target effects would be to use modified forms of the CRISPR protein to switch off the PCSK9 gene without altering its DNA. Instead of changing the genome, this kind of editing targets the epigenome instead, the chemical “tags” added to DNA that influence how active particular genes are. Many think epigenome editing will prove more useful than conventional genome editing for treating diseases. “I think the future is CRISPR 3.0 and 4.0,” said Lorenz Mayr, referring to epigenome editing.