Scientists have edited a gene that may reduce high cholesterol permanently

With a snip of a gene, doctors may one day permanently lower dangerously high cholesterol, possibly removing the need for medication, according to a new pilot study published Saturday in the New England Journal of Medicine.

The study was extremely small — only 15 patients with severe disease — and was meant to test the safety of a new medication delivered by CRISPR-Cas9, a biological sort of scissor which cuts a targeted gene to modify or turn it on or off.

Preliminary results, however, showed nearly a 50% reduction in low-density lipoprotein, or LDL, the “bad” cholesterol which plays a major role in heart disease — the No.1 killer of adults in the United States and worldwide.

The study, which will be presented Saturday at the American Heart Association Scientific Sessions in New Orleans, also found an average 55% reduction in triglycerides, a different type of fat in the blood that is also linked to an increased risk of cardiovascular disease.

“We hope this is a permanent solution, where younger people with severe disease can undergo a ‘one and done’ gene therapy and have reduced 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 Heart, Vascular & Thoracic Institute at Cleveland Clinic in Ohio.

“That’s a dream come true,” Nissen said. “If you’d asked me 15 years ago if we could have done something like this, I would have thought you were crazy,”

Today, cardiologists want people with existing heart disease or those born with a predisposition for hard-to-control cholesterol to lower their LDL well below 100, which is the average in the US, said Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School in Boston.

“There is evidence to suggest that the optimal cholesterol level is 40 to 50, which is very hard to do through diet and lifestyle,” said Natarajan, who was not involved in the study.

“Now, today’s medications can already lower LDL cholesterol to the levels found in the study — in fact, some medicines are a little more potent,” he said. “So we’re going to have to wait and see if this treatment works as well as this first study suggests.”

While early, the findings are exciting due to the difficulty of remembering to take a daily medication — and sometimes three or four — to control high cholesterol levels, said preventive cardiologist Dr. Ann Marie Navar, an associate professor of cardiology at UT Southwestern Medical Center in Dallas, Texas.

“In spite of having a lot of available therapies, the majority of people do not have their LDL under control,” said Navar, who was not involved in the study.

“If you’re 20 and you have really high cholesterol, it may make a lot more sense to have a one-time treatment that doesn’t require you to have to take a pill every single day or shot every two weeks for the next 60 years,” she said. “The potential for this is just enormous.”

A lucky mutation to reduce high cholesterol

The idea for a gene-editing treatment came from an unusual source — a genetic mutation. In that scenario, the ANGPTL3, or angiopoietin-like protein 3 gene, which is responsible for regulating LDL and triglycerides is shut off.

People with a nonfunctioning ANGPTL3 gene — which Natarajan says applies to about 1 in 250 people in the US — have lifelong levels of low LDL cholesterol and triglycerides without any apparent negative consequences. They also have exceedingly low or no risk for cardiovascular disease.

“It’s a naturally occurring mutation that’s protective against cardiovascular disease,” said Nissen, who holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic. “And now that CRISPR is here, we have the ability to change other people’s genes so they too can have this protection.”

Various doses of the CRISPR-based drug were given to study participants by infusion: One set of people received a very tiny dose of 0.1 milligrams per kilogram, while others received levels from 0.3 to 0.8 milligrams per kilogram, said lead study author Dr. Luke Laffin, a preventive cardiologist at Cleveland Clinic’s Heart, Vascular & Thoracic Institute.

“The average 55% decrease in triglycerides and nearly 50% in LDL cholesterol occurred at the highest dose,” Laffin said. “That’s exciting because there are no therapies available now that simultaneously lower LDL cholesterol and triglycerides.”

There was a small decrease in HDL (high density lipoprotein), which is known as “good” cholesterol. However the drop in HDL is also found in people with the ANGPTL3 mutation and doesn’t appear to be harmful, Laffin said.

“The most common disorder that we see in our prevention clinic is mixed hyperlipidemia —people who have trouble controlling both their LDL and triglycerides,” Nissen said. “So to be able to do this simultaneously is really an important development.”

Long-term safety profile

In people with the natural mutation, the ANGPTL3 gene is turned off in every cell in the body — muscles, heart, lungs and so forth. The new medication, however, targets only the liver, the organ responsible for synthesizing triglycerides and producing cholesterol while also removing excess cholesterol from the bloodstream.

That’s reassuring for the long-term safety of the drug’s impact, Nissen said, making it less likely that genes in other parts of the body could also be edited.

Side effects of the initial treatment were minimal, mostly irritation at infusion sites, according to the study. One person suffered a spinal disk herniation, and another had an increase in enzymes that could signal liver damage, but those levels resolved within two weeks.

However, one person died six months after the infusion: “He had extensive, advanced cardiovascular disease, and he got the tiniest 0.1 dose, a dose that doesn’t do anything,” Nissen said.

“We don’t think that his death has any implications to the study at all,” he said. “In addition, the FDA has recommended these people be followed after the trials are all over for 15 years to see if there are long term adverse effects. That will be done, and it’s the right thing.”

Phase 2 clinical trials will begin soon, quickly followed by Phase 3 trials, which are designed to show the effect of the drug on a larger population, Nissen said.

“We hope to do all this by the end of next year,” Nissen said. “We’re moving very fast because this is a huge unmet medical need — millions of people have these disorders and many of them are not on treatment or have stopped treatment for whatever reason. That’s a huge under treatment issue here in the United States.”

Still, this is early days, and there have been similar drugs which looked promising at the beginning but were later rejected due to safety concerns, Nadar said.

“The most important take home message is if you’re on a cholesterol lowering medication, stay on it,” she said. “All the data show the longer you lower your LDL cholesterol, the better your outcome. Someone who lowers their LDL from 100 to 30 for a only year is going to be far less protected than someone who lowered their cholesterol from 100 to 50 for a lifetime.”

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