Limone is a gorgeous Italian town tucked between rocky cliffs and Lake Garda, popular with tourists for its beautiful views, pebble beaches, café terraces, and picturesque churches. The resort town’s exports include lemons, olives, and olive oil—and an incredibly useful gene mutation.
About 40 of the town’s inhabitants have an unusual gene mutation that keeps their arteries from getting clogged. The mutation protects them from the world’s leading cause of death: heart disease.
Dr. P.K. Shah is the director of the Atherosclerosis Research Center at the Smidt Heart Institute. He and his colleagues have been studying this gene since the 1990s, looking for ways the mutation could be used to help reverse and prevent heart disease. One focus of his current atherosclerosis research is gene therapy.
What is this gene?
Dr. Shah: This particular gene helps the body make a protein that’s found in the high-density cholesterol—or the “good” cholesterol—in our bodies.
People with the mutation in this gene have an even more powerful version of this protein that keeps their arteries clear of the plaque that clogs the blood vessels of so many people, leading to heart attacks and strokes.
How does it help prevent clogged arteries?
Dr. Shah: It works in 3 ways. First, it stimulates the removal of cholesterol from the arteries, and this cholesterol is then transported to the liver, where it’s processed and excreted from the body instead of staying in the blood vessels and turning into plaque.
It also suppresses inflammation, which contributes to hardening of the arteries.
Lastly, it helps modulate the immune system, so the immune system doesn’t overreact and contribute to plaque building up.
What have your studies with gene therapy found so far?
Dr. Shah: We’re studying how transferring the gene into mice is affecting their arteries. In one study, our control group had very clogged arteries. We gave another group the regular version of the gene that makes this protein. In those mice, their arteries partly cleared. In another group, we gave them the mutated version of the gene. In these mice, their arteries cleared almost completely.
In another model, mice were fed a high-fat diet for 14 weeks. We divided them into two groups. One group ate a normal diet for the next 20 weeks. We saw some improvement in their arteries, but basically a minimal change. The other group ate the same normal diet and got the mutated gene as well. Their arteries cleared of plaque almost completely.
How can this help people in the future?
Dr. Shah: The goal is to bring this kind of treatment into the clinic, where it can prevent or reverse plaque buildup. Plaque buildup is the leading cause of stroke and heart attack. In fact, heart disease is the leading cause of death worldwide.
We’ve tried to find ways in the past of using this mutation. One way would be to manufacture the protein that the mutated gene produces, and then infuse the protein into the patients. However, you’d have to make so much and it would be so expensive, it hasn’t worked well yet.
What we’d like to see is a gene therapy method that would introduce the gene into the body, and then people would make their own version of this protein and get all the benefits enjoyed by the Italian people born with the mutation.