According to a new pilot study published Saturday in the New England Journal of Medicine, doctors may one day be able to permanently lower dangerously high cholesterol levels, possibly eliminating the need for medication.
The trial was very small – just 15 patients with severe disease – and was designed to test the safety of a new drug delivered using CRISPR-Cas9, a biological type of scissors that cuts through a target gene, to modify or turn it on or off.
But preliminary results showed a nearly 50% drop in low-density lipoprotein, or LDL, the “bad” cholesterol that plays a major role in heart disease, the No. 1 killer of adults in the U.S. and worldwide.
The study, which will be presented Saturday at the American Heart Association’s Scientific Sessions in New Orleans, also showed an average 55 percent reduction in blood triglycerides, another type of fat that is also associated with an increased risk of cardiovascular disease.
“We hope this is a permanent solution where younger people with severe disease can have ‘one-and-done’ gene therapy and lower LDL and triglycerides for the rest of their lives,” said senior study author Dr. Steven Nissen, chief academic officer of the Sydell and Arnold Miller Family Cardiovascular and Thoracic Institute at the Cleveland Clinic in Ohio.
“It’s a dream come true,” Nissen said. “If you had asked me 15 years ago if we could do something like this, I would have thought you were crazy.”
Today, cardiologists want people with heart disease or a predisposition to hard-to-control cholesterol to lower their LDL well below 100, which is the U.S. average, said Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital and professor of medicine at Harvard Medical School in Boston.
“There is evidence that the optimal cholesterol level is 40 to 50, which is very difficult to achieve with diet and lifestyle,” said Natarajan, who was not involved in the study.
“Now, today’s drugs can already lower LDL cholesterol to the levels found in the study — in fact, some drugs are a little bit stronger,” he said. “So we’ll have to wait and see if this treatment works as well as this first study suggests.”
Although early, the findings are interesting because it’s hard to remember to take medications (sometimes three or four) to control high cholesterol every day, said preventive cardiologist Dr. Ann Marie Navar, MD, associate professor of cardiology at UT Southwestern Medical Center in Dallas, Texas.
“Despite the availability of many treatments, most people do not have their LDL under control,” said Navarre, who was not involved in the study.
“If you’re in your 20s and you have really high cholesterol, it might make a lot more sense to do a one-time treatment where you don’t have to take a pill every day or an injection every two weeks for the next 60 years,” she said. “The potential for this is just huge.”
A lucky mutation that lowers high cholesterol
The idea of gene editing treatment came from an unusual source – genetic mutation. In this case, the ANGPTL3 or angiopoietin-like protein 3 gene responsible for regulating LDL and triglycerides is turned off.
People with a malfunctioning ANGPTL3 gene, which Natarajan said affects about 1 in 250 people in the U.S., have low LDL cholesterol and triglycerides throughout their lives with no apparent ill effects. They also have a very low risk of cardiovascular disease.
“This is a naturally occurring mutation that protects against cardiovascular disease,” said Nissen, the Lewis and Patricia Dickey Endowed Chair in Cardiovascular Medicine at the Cleveland Clinic. “And now that CRISPR is here, we have the ability to change other people’s genes so that they can also have this protection.”
Different doses of the CRISPR-based drug were given by infusion to study participants: one group of people received a very low dose of 0.1 milligrams per kilogram, while others received between 0.3 and 0.8 milligrams per kilogram, said the study’s lead author, Dr. Luke Laffin, a preventive cardiologist at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute.
“Mean triglycerides were reduced by 55% and LDL cholesterol was reduced by almost 50% at the highest dose,” Laffin said. “This is interesting because there are currently no treatments that reduce LDL cholesterol and triglycerides at the same time.”
There was a slight decrease in HDL (high-density lipoprotein), the so-called “good” cholesterol. However, the reduction in HDL is also seen in people with the ANGPTL3 mutation and does not appear to be harmful, Laffin said.
“The most common disorder we see in our prevention clinic is mixed hyperlipidemia — people who have trouble controlling their LDL and triglycerides,” Nissen said. “So to be able to do that at the same time is a really important change.”
Long-term safety profile
In people with the natural mutation, the ANGPTL3 gene is turned off in every cell in the body—muscle, heart, lungs, and more. However, the new drug only targets the liver, the organ responsible for triglyceride synthesis and cholesterol production, as well as removing excess cholesterol from the bloodstream.
That’s reassuring about the long-term safety of the drug, Nissen said, making it less likely that genes in other parts of the body could also be edited.
According to the study, side effects from the initial treatment were minimal, mainly irritation at the infusion sites. One person suffered a herniated disc in the spine and another had elevated levels of enzymes that can signal liver damage, but these levels resolved within two weeks.
But one person died six months after the infusion: “He had extensive, advanced cardiovascular disease and received the lowest dose of 0.1, a dose that does nothing,” Nissen said.
“We don’t think his death has any implications for the investigation,” he said. “Also, the FDA has recommended that these people be followed up after the 15-year trials to see if there are any long-term adverse effects. That will be done, and it’s the right thing to do.”
Phase 2 clinical trials will begin soon, followed quickly by Phase 3 trials to show the drug’s effects in a larger population, Nissen said.
“We hope to have it all done by the end of next year,” Nissen said. “We’re moving very quickly because this is a huge unmet medical need—millions of people have these disorders and many are untreated or have stopped treatment for whatever reason. It’s a huge treatment problem in the United States.”
Still, it’s early days, and there have been similar drugs that initially looked promising but were later rejected because of safety concerns, Nadar said.
“The most important message is if you’re on cholesterol-lowering medication, take it,” she said. “All the data show that the longer you keep your LDL cholesterol down, the better the results. Someone who gets their LDL cholesterol down from 100 to 30 for one year will be much less protected than someone who gets their LDL cholesterol down from 100 to 50 over a lifetime.”
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