For the first time, gene-editing provides hints for lowering cholesterol

For the first time, researchers have produced evidence that gene-editing can cut high cholesterol, a major risk factor for the nation's leading killer.

Preliminary results from a study involving 10 patients born with a genetic condition that causes very high cholesterol found that editing a gene inside the liver can significantly reduce levels of "bad cholesterol."

The experimental treatment needs to be tested on more patients who would be followed for much longer to confirm the approach is safe and effective. But the results are being hailed as a potential landmark proof-of-concept that could eventually provide a powerful new way to prevent heart attacks and strokes.

"These data are really very exciting," says Dr. Deepak Bhatt, director of the Mount Sinai Fuster Heart Hospital and a professor of cardiovascular medicine at Icahn School of Medicine at Mount Sinai in New York.

Bhatt, who was not involved in the research, stressed that much more research is needed to resolve important open questions. However, "this could have an enormous impact on cardiovascular disease," Bhatt says.

A new way to treat heart disease

The data from the highly anticipated study, which is being conducted by Verve Therapeutics, Inc., in Boston, were presented Sunday at an American Heart Association meeting in Philadelphia.

"What we're trying to do is develop an entirely new way to treat heart disease," Dr. Sekar Kathiresan, Verve's executive officer, told NPR in an interview. "We're super excited. This is the first-ever evidence that one can actually rewrite a single DNA letter in the human liver and have a clinical effect. So we're thrilled."

But some other independent scientists also remain cautious.

"Hopefully it will work. But there are many many aspects that are really still fuzzy," including the long-term safety, says Dr. Eric Topol, a cardiologist and professor of molecular medicine at Scripps Research in California. "There's considerable uncertainty here."

Heart disease kills about 695,000 people each year in the U.S.

High levels of a form of cholesterol known as low-density lipoprotein (LDL) cholesterol narrow arteries, blocking blood to the heart and brain and setting the stage for heart attacks and strokes.

Verve studied patients born with familial hypercholesterolemia, a genetic disorder that affects an estimated 1-in-250 people, which causes extremely high LDL.

Patients can take drugs, including a popular class known as statins, to reduce LDL levels. But while those drugs are very safe and effective, many patients fail to take them regularly as needed, leaving them vulnerable. So the hope is the gene-editing treatment could not only treat those with the genetic condition, but also provide a one-time therapy for anyone at risk.

"This same medication should be helpful for any garden-variety patient without the genetic disease," says Kathiresan.

Researchers used a form of gene-editing known as CRISPR, which enables scientists to make very precise changes in DNA much more easily than ever before. Specifically, they used a newer version of CRISPR known as "base-editing," which gives scientists the power to rewrite individual letters in the genetic code.

In this case, the editing occurred in liver cells in the organ inside the body. Other approaches to gene-editing have required removing cells from the body, editing them in the lab and then infusing them back into patients.

For the trial, which is ongoing, scientists are infusing different doses of a CRISPR base-editing molecule that makes it way to the liver to edit a gene called PCSK9, which is necessary for the production of LDL cholesterol.

Of the 10 patients treated so far, ages 29 to 69, all were in the United Kingdom and New Zealand. Only three of the patients received a dose high enough to cause a beneficial reduction in LDL. Two patients experienced reductions in their LDL levels of 39% and 48%. The one patient who received the highest dose experienced a reduction in LDL of 55% that has lasted at least six months so far.

"This is really the first-ever evidence that one can actually rewrite a single DNA letter in the liver of a living human being and have a clinical effect," Kathiresan.

Mohammed Kahn, 47, of London, was one of the most recent patients treated in the study. Kahn's father died at age 42 and two of his older brothers have already had heart attacks. Kahn's already had a procedure to treat narrowed arteries to his heart.

"It's a brilliant approach," Kahn said in an interview with NPR. "It's fantastic. I hope for the best. I'm very very optimistic that this will be working in my body."

Cholesterol treatment is just the beginning

Gene-editing is generating enormous excitement because the technique could lead to new treatments for many genetic diseases, including cancer, heart disease, AIDS, Alzheimer's and other ailments.

In fact, the Food and Drug Administration is poised to approve the first gene-editing treatment next month for the devastating blood disorder sickle cell disease.

"This is exciting for Verve, for the patients, but also more broadly if you look at my entire field," says Fyodor Urnov, professor of molecular therapeutics at University of California, Berkeley.

When he heard about the study's results, Urnov says, "My heart skipped a beat in a good way, in the hopes that these data are the first step towards a future where many peoples heart don't skip a beat and remain healthier for longer."

But others caution this approach faces a higher bar than the sickle cell treatment, especially because both are expected to cost millions of dollars per patient. Unlike for sickle cell, there are already very safe, effective and inexpensive cholesterol-lowering drugs for heart disease.

One key worry is the editing may cause inadvertent genetic changes known as "off-target" effects that could cause health problems years later.

"We don't know much about off-target effects of genome-editing," Topol says. "So even though this is targeting a specific gene that is tied to very high cholesterol, it could have other effects in the genome that are unintended."

"There are a lot of uncertainties. This is a very bold approach but we'll have to see," Topol says.