Genetically engineered immune cells could help reduce the clogging of arteries, potentially lowering the risk of heart attack or stroke in people who don’t respond to common treatments.
Doctors often treat those at high risk of these conditions using drugs called statins, but they don’t protect everyone. “If statins were perfect we wouldn’t have such an issue with cardiovascular disease – it’s still the leading cause of death worldwide,“ says at the University of Pennsylvania.
Many cardiovascular conditions are caused by the build-up of fatty deposits called plaques on artery walls, which can restrict blood flow to major organs. Statins and some other drugs work by lowering levels of low-density lipoprotein (LDL), or “bad” cholesterol, a key component of plaques. However, they don’t effectively suppress inflammatory immune cells within plaques. That is a problem because researchers are increasingly recognising these cells as major drivers of plaque build-up, or atherosclerosis, says Schwab.
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To address this, he and his colleagues collected immune cells, called T-cells, from mice and genetically tweaked them to release anti-inflammatory proteins in the presence of LDL cholesterol.
Next, the researchers injected two doses of the engineered cells, which are known as CAR T-cells, into each of four mice over five weeks, while feeding the animals a high-fat diet that causes atherosclerosis. To prevent the animals’ immune systems from rejecting the transferred cells, the team gave them an immunosuppressive drug, called cyclophosphamide, just before each injection. As a control group, the researchers gave the same treatment to four other mice, but with CAR T-cells designed to activate in the presence of a protein not found in mice, meaning they should stay dormant.
After another five weeks, the researchers found that arteries extracted from the first group of mice contained 80 per cent less plaque, on average, than those from the second. “The LDL-targeted T-cells substantially reduced plaque build-up, without major side effects,” says Schwab.
By analysing blood from the mice, the team found that levels of LDL cholesterol were similar in both groups, indicating that the therapy worked by suppressing inflammation, says Schwab, rather than reducing cholesterol.
“The study does a good job of confirming the important role of inflammation in atherosclerosis,” says at King’s College London. “It’s been quite hard to actually pin down how important that is and whether any therapies might really influence it.”
The results hint that the approach could cut the clogging of arteries in people who don’t benefit much from standard drugs, says Ferro.
But larger studies in animals should verify the results before it is tested in humans, says at the University of Bristol, UK. “There are differences in atherosclerosis between mice and humans – we know many treatments fail in clinical trials,” he says.
If everything goes smoothly, Schwab says his team hopes to test the approach in people in the next couple of years.
bioRxiv
