Experimental Gene Therapy May Help Fight Inherited High Cholesterol

Scientists are testing an injectable gene therapy that may block the production of lipoprotein(a) in people whose levels are dangerously high.

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Small Trial Shows Gene Silencing Therapy Reduces Lipoprotein-a
Gene therapy shows promise as a treatment for people with genetically high Lp(a).Getty Images

A new gene therapy may one day be used to reduce blood levels of lipoprotein(a) in individuals who have inherited forms of high cholesterol that cause heart disease early in life, judging by the results of a small clinical trial.

The injected drug — so new it’s labeled SLN360 and has not yet been named — works by deactivating the gene responsible for lipoprotein(a) production.

Patients who received higher doses of this drug saw their lipoprotein(a) levels drop by as much as 98 percent, according to preliminary trial results published April 3 in the Journal of the American Medical Association (JAMA). Five months later, these patients still had lipoprotein(a) levels 71 to 81 percent lower than before they received the drug.

“You can’t alter lipoprotein(a) with diet or lifestyle changes. Historically, it’s been considered untreatable,” says the lead study author,?Steven Nissen, MD, the chief academic officer of the heart, vascular and thoracic institute at Cleveland Clinic in Ohio. “We have been wanting to tackle this for decades.”

One in four people worldwide have high lipoprotein(a) cholesterol, Dr. Nissen says.

Messenger RNA Therapy Is Also Used in COVID-19 Vaccines

Lipoprotein(a) — or Lp(a) — has some similarities to the “bad” cholesterol known as low-density lipoprotein (LDL). Both types of cholesterol can build up in blood vessels and lead to blood clots and heart attacks. Unlike LDL, which can accumulate over time in those with an unhealthy lifestyle, Lp(a) levels are almost entirely determined by genetics and are present from birth.

The new drug targeting Lp(a) is what’s known as a small interfering RNA (siRNA) therapy that works by silencing the gene that tells the body to make this type of cholesterol. This technology acts on what’s known as messenger RNA (mRNA), a type of RNA that uses information inside genes to create blueprints for the manufacture of proteins.

If mRNA sounds familiar, that may be because it’s at work in the Pfizer-BioNTech and Moderna COVID-19 vaccines. With these vaccines, mRNA ramps up production of a protein that helps our immune system battle the virus. With this new Lp(a) therapy, mRNA is silenced to halt production of a harmful protein.

“Both cases involve messenger RNA,” Nissen says. “In the case of Lp(a) we are interfering with messenger RNA to stop production of the harmful protein — it’s exactly the opposite of what happens with a vaccine.”

Small Trial Shows Promise for Future Research

Researchers tested their experimental gene therapy in 32 adults who all had Lp(a) levels above 150 nanomoles per liter (nmol/L) — twice the level considered normal. None of the participants had a history of heart disease. Eight people received a placebo injection, and the remaining participants received one of four different doses of the gene therapy.

People who took the highest doses of the drug — 300 milligrams (mg) and 600 mg — had Lp(a) levels drop by 96 percent and 98 percent, respectively. In addition, participants who received these doses saw their LDL cholesterol levels drop by 20 to 25 percent.

Participants who got the placebo injection saw no change in Lp(a) levels.

Side effects were generally mild and most often involved either injection site soreness or headache. Scientists are continuing to monitor participants to collect follow-up data after one year.

If the results seen from this early test in a handful of patients hold up over longer, larger trials, it’s possible that a gene silencing therapy for high Lp(a) might be available for patients within three or four years, Nissen says.

Lipoprotein(a) Blood Tests Are Not Routine

One challenge with introducing a new treatment targeting Lp(a) is that doctors don’t currently screen for this type of cholesterol, says Brian Ference, MD, the author of an editorial accompanying the study in JAMA, a professor, and the director of research in translational therapeutics at the University of Cambridge in England. Another challenge is that it’s not yet clear exactly how low Lp(a) needs to go to make a big difference in patients’ risk of heart attack and stroke.

“Most physicians are either unaware that elevated Lp(a) levels are strongly associated with an increased risk of cardiovascular events, uncertain how to interpret a patient’s Lp(a) level, or uncertain about how to treat an elevated Lp(a) level,” Dr. Ference says.

SLN360, the drug tested in the current trial, is one of several experimental therapies that use mRNA to halt production of Lp(a) cholesterol, Ference says. Most likely, these drugs would be used only in a subset of people with genetically high Lp(a), which might include individuals with an inherited form of high cholesterol known as family hypercholesterolemia.

“These novel therapies have the potential to substantially reduce the risk of heart attack and stroke among persons with markedly elevated Lp(a) and will likely change practice, because there are currently no treatments available that can substantially and specifically lower Lp(a) levels,” Ference says.

Cholesterol screening protocols would likely change once treatments for elevated Lp(a) are widely available, Nissen notes. Because high Lp(a) is due to genetics, it will be important for anyone who has this type of high cholesterol to urge their parents, siblings, and children to get tested. In many cases, people will have no symptoms until they have a heart attack.

“It’s passed down through families,” Nissen says. “Often I will test children in their teen years and their levels will be sky high.”

Lifestyle Choices Still Matter

Even if people one day can get treatment for high Lp(a) cholesterol that runs in families, this doesn’t necessarily mean they can stop worrying about their risk of heart disease, says Anthony DeMaria, MD, the chair of cardiology at the University of California in San Diego and a past president of the American College of Cardiology.

“Lifestyle modifications are always the first step in controlling any metabolic abnormality, and this would include Lp(a),” Dr. DeMaria says. People with high Lp(a) may also have elevated LDL cholesterol that requires treatment with a statin drug, DeMaria adds.

There are several lifestyle changes that can help control LDL cholesterol, according to the Mayo Clinic. These include:

  • Eat a heart-healthy diet. This means eliminating trans fats found in oils and margarine, reducing saturated fats found in red meats, eating fish and other foods high in omega-3 fatty acids, getting more fiber, and eating dairy products with whey protein.
  • Get lots of exercise. You should aim for either 30 minutes of moderate activity five times a week or 20 minutes of intense exercise three days a week.
  • Quit smoking.
  • Maintain a healthy weight.
  • Drink alcohol in moderation.

All these habits are a good idea even if the cause of high cholesterol is genetic and involves elevated Lp(a), Ference says.

“It is important to recognize that the effect of LDL and Lp(a) on the risk of heart attack and stroke are largely independent,” Ference says. “Therefore, lowering Lp(a) is not a substitute for lowering LDL.”