A gene-editing "vaccine" could stop the world's leading killer

As many as 50 percent of heart attacks strike without any warning signs and in individuals with no history of heart disease. When it comes to fatal heart attacks, the victim’s genes often drive this tragic turn of events. But imagine a world where years before someone’s heart malfunctions, a single infusion reduced their risk of a heart attack by up to 90 percent. That’s the moonshot Dr. Kiran Musunuru is aiming for: the world's first heart attack "vaccine."

"Cardiovascular disease is the preeminent global health threat of the 21st century. It is going to happen and the only way you can combat a threat of that magnitude is to use what has worked so well in the 20th century for certain infectious diseases — a vaccination style program," Musunuru tells Inverse.

For the past 12 years, Musunuru, a cardiologist and researcher at the University of Pennsylvania, has worked to harness CRISPR gene-editing technology to “turn off” bad genes associated with heart attack risk.

It’s not a vaccine in the traditional sense — it doesn’t activate the immune system. But, like a vaccine, the concept hinges on a single dose therapy that could confer “enduring and possibly lifelong protection against heart disease,” Musunuru says.

“It's not like we're trying to do something totally crazy and offbeat and unproven,” the researcher explains. A small number of lucky individuals are actually born without these risky genes, and they’re perfectly healthy.

“We’re looking to nature and looking to what's happening in the general population with those ‘genetic superheroes’ who have the gene naturally turned off.”

Musunuru hopes to edit the DNA of people who are at risk for heart disease or have active heart disease. In the future, people could still get heart attacks from unhealthy diets, lack of exercise, and environmental factors like pollution. But through this "vaccine" the potentially harmful genes linked to heart attacks would be effectively neutralized before they could cause any harm.

"It's not like we're trying to do something totally crazy."

Essentially, Musunuru explains, his team is trying to take what the fortunate few who have won the genetic lottery were born with, and extend that to the rest of the population.

Currently, this process only works in mice. But if the technique is successfully used to edit the human genome, it could radically change the lifespan and quality of life for millions of people around the world at risk of heart disease.

Broken hearts

Heart disease is the leading cause of death, for men and women, worldwide, according to the World Health Organization. That means heart attacks take more lives than other potent killers like stroke, cancer, and diabetes. After years of steady decline, heart disease is rising again, even in young people — a trend driven by obesity, diabetes, and high blood pressure.

"I think it's going to be the way of the future."

What causes heart disease is split between environment and genes, Musunuru tells Inverse. Environmental factors include habits like smoking and poor diet, as well as pollution. Certain genes, like PCSK9 and ANGPTL3, which are stored in the liver, can spike LDL cholesterol and triglycerides (fats), which contribute to heart attacks.

To create a heart attack vaccine, Musunuru is harnessing the power of CRISPR-cas9, a gene-editing tool that has both spurred huge wins in medicine and contributed to controversy, to eliminate these heart disease-related genes.

"If you could take out a gene that just produces LDL cholesterol, it could be totally game-changing," Holly Andersen, a cardiologist at New York-Presbyterian Hospital and Weill-Cornell Medical Center, tells Inverse.

"And so far, I think CRISPR is pretty safe, simple, and amazingly effective. I think it's going to be the way of the future."

CRISPR stands for clustered regularly interspaced short palindromic repeats. These are found in bacteria's DNA. Meanwhile, Cas9 is an enzyme that can snip DNA like a pair of molecular scissors. Together, they make for a naturally occurring genome editing system in bacteria.

The technology that experts use to edit parts of the genome is called CRISPR-Cas9, often simply referred to as CRISPR, and was inspired by that natural process. CRISPR is already used across the agricultural sector and the first human CRISPR trials kicked off in 2018. These involved leveraging the tool to treat patients with cancer, blood disorders, and sickle-cell anemia.

Since 2014, Musunuru and his team have explored how CRISPR can improve heart health. So far, the journey is going well: In mice, the team was able to effectively “turn off” the PCSK9 gene, dropping mice’s LDL cholesterol levels (the “bad” cholesterol) by 40 percent, as shown in a study published in the journal Circulation Research in 2015.

In mice, they've also been able to edit the ANGPTL3 gene and reduce levels of triglycerides by 35 percent, according to a 2018 study published in Circulation.

Currently, there are other medications for heart disease patients, called PCSK9 inhibitors, that effectively do the same thing. But these drugs are expensive and need to be injected every few weeks.

Unlike humans, mice don’t get heart attacks, limiting the studies' implications in humans. To get closer to modeling the human body, Musunuru injected human liver cells in the mice’s bloodstream, creating “humanized mice.” These mice were modified to carry around mini-livers derived from human cells and, in turn, the CRISPR technique successfully turned off the targeted genes and lowered the mice’s cholesterol.

These results signal the technique is likely to work effectively in humans, Musunuru says, but only human trials can confirm the promising findings.

Next stop: humans

The biggest safety concern when it comes to CRISPR are “off-target effects.” That would be when the tool misses the mark or accidentally alters other parts of the genome. But, so far, research hasn’t shown any untoward consequences whatsoever, Musunuru says. The risk of these mistakes manifesting in health problems is “more of a theoretical concern.”

Still, Musunuru stresses his team is investigating this possibility of these and any other downstream effects closely before they ever go anywhere near a human.

“While promising and potentially revolutionary, this approach will require several years of validation efforts,” Amit V. Khera, a cardiologist and human geneticist at Massachusetts General Hospital, tells Inverse.

What the team will have to do, Khera explains, is "get the mutation into the liver and prove that cholesterol is reduced by a clinically meaningful amount. Then the scientists will have to confirm that it is therapeutic and safe.

"It will be permanent and they'll have lifelong protection against heart attacks."

If the research goes as planned — meaning no major off-target effects or unforeseen outcomes — Musunuru hopes to test the technique in humans in as little as three years. If the treatment works in humans, it may be available to patients in a decade or two.

And, down the line, if the vaccine is offered to every adult, it could drastically improve life expectancy across the population.

“If enough people take it, they'll immediately have their cholesterol levels and maybe their triglyceride levels fall," Musunuru says. "It will be permanent and they'll have lifelong protection against heart attacks.”

The vaccine doesn’t eliminate the risk entirely, but may “push off any heart attack by decades,” he says.

Andersen stresses that, even if this technique does become accessible, people will still need to maintain a healthy diet and healthy levels of physical activity to generally prevent diseases and combat aging.

“So although this can help prevent plaque buildup, it doesn't give you a license to not take care of yourself," she says.

From the lab to the clinic

Initially, the heart attack vaccine won’t be offered to “every person on the street who wants it," Musunuru emphasizes.

He predicts the therapy will be given to people in the acute aftermath of a heart attack — those who are actually recovering in a hospital bed. Currently, patients are typically discharged with a statin prescription after experiencing a heart attack. Statins are common, daily medications that lower cholesterol.

But within a year after a heart attack, 50 percent of patients stop taking their statins, often because of cost or accessibility issues, Musunuru explains. He predicts that the heart attack vaccine could be a one-time solution to prevent prescription drop off, and help people get lasting heart protection without a daily pill.

“This treatment could actually be an equalizer,” Musunuru says. “It could actually, to some degree, address socioeconomic inequalities with respect to the health care system.”

He hopes that the therapy would be offered to people with risky genes, and eventually, everyone.

When it arrives, the heart attack vaccine won't exactly look like a flu shot. The delivery method will likely include an infusion through an IV rather than a single needle jab. In theory, the cardio-protective effects would kick in within a few days of the infusion, and last a lifetime.

If the injection is safe and effective in humans — and that's still an if — it could prevent early deaths, hospitalizations, and the grief of losing a loved one too soon.