What’s next for CRISPR? A Penn cardiologist wants to edit the genes of people with high cholesterol.

The FDA just approved the first treatment that involves editing a person’s genes, using CRISPR technology to reduce — even eliminate — the debilitating symptoms of sickle cell disease.

Could high cholesterol be next?

That’s the hope of Penn Medicine cardiologist Kiran Musunuru, who cofounded the gene-editing startup Verve Therapeutics in 2019.

In November, the Boston-based company said levels of LDL cholesterol (the “bad” kind) had dropped sharply in three patients who received an experimental CRISPR treatment. But the study was preliminary, and it could be years before it and other such gene-editing therapies are approved.

The sickle cell treatment was a special case, as patients’ stem cells are removed from the body, edited, and carefully tested before they are reinfused. CRISPR treatments such as the one for high cholesterol are a bigger challenge, as they involve editing a gene inside the person’s body.

In the Verve study, the three people whose LDL cholesterol levels improved all received fairly high doses of the treatment. Six other participants who got lower doses saw little to no reduction in their cholesterol levels. That type of “dose-response” relationship — meaning there was a larger apparent impact at higher doses — suggests the treatment is likely working.

Yet the trial also saw two adverse events: one participant died of cardiac arrest five weeks after getting the therapy, and another had a heart attack the day after treatment but has since recovered.

In an interview, Musunuru explained why the results of the Verve trial were still promising. He also spoke about what’s next for the field of CRISPR, and how it relies on a technology that was used in the Pfizer and Moderna vaccines for COVID-19.

Musunuru is not employed by Verve but is an advisor to the company and has a stake in it. He was not involved in conducting the preliminary cholesterol study, and his comments were based solely on what the company disclosed in November.

A professor of cardiovascular medicine and genetics at Penn’s Perelman School of Medicine, he also is collaborating with Children’s Hospital of Philadelphia to study the use of CRISPR for treating three infant metabolic diseases. In August, the team received a $26 million National Institutes of Health grant for that project.

This conversation has been edited for length and clarity.

There are two forms of this condition, called familial hypercholesterolemia. People with the more severe form have a mutation in both copies of a gene for a protein that takes cholesterol out of the blood. The cholesterol just stays in the bloodstream.

In the less severe form, one copy of that gene is inactivated or mutated. You have high LDL cholesterol levels but not as high as in the severe form. You’re talking above 200 [mg/dL] or so. With the severe form, you’re talking above 500.

Cholesterol in the bloodstream can end up in the walls of the coronary artery. Then you start to develop plaque, and when the plaque ruptures, that’s when you get a heart attack.

There’s an estimated 1 to 2 million people in the United States who have the less severe form of the disease. Most of them don’t know it. They don’t have their cholesterol levels checked routinely. That’s going to greatly increase your risk of getting a heart attack.

[The CRISPR treatment that Verve has started testing is designed for people with the less severe form of the disease. A different version is in the works for people with the more severe form of the disease.]

The COVID-19 vaccines consist of messenger RNA that’s carried inside tiny droplets called lipid nanoparticles. You get a jab in the arm, and the mRNA ends up in local immune cells, where they start producing the spike protein of the coronavirus.

With Verve’s CRISPR approach and others like it, it’s the same technology, with the mRNA carried by lipid nanoparticles. Except your mRNA, instead of encoding the spike protein, it encodes CRISPR. The lipid nanoparticles go straight to your liver. Once there, the mRNA starts making CRISPR.

In Verve’s CRISPR treatment, it’s turning off a gene called PCSK9. It changes exactly one letter out of 3 billion in the genome. By changing that one letter in exactly the right place, it turns it off.

» READ MORE: This girl's cholesterol was over 800. Could it be treated with CRISPR?

The one patient who died, that was five weeks after getting the treatment. There’s very little reason to think it has anything to do with the treatment. The nature of the treatment is such that it clears out of the body within a few days. This is the sort of thing where if the patient hadn’t gotten the treatment, this would’ve happened anyway.

The other one is trickier. That patient was diagnosed with a heart attack the day after the treatment. But it turns out this patient was having chest pain for the week leading up to getting the treatment. If you’re having chest pains, something is going on. That’s not a good thing.

Evidently this particular patient didn’t tell the investigators they were having chest pain. If they had told them they were having chest pain, they would not have gotten the treatment.

One of them is a metabolic condition called phenylketonuria (PKU), in which patients cannot break down an amino acid called phenylalanine. When the phenylalanine builds up, it is toxic to the brain.

With CRISPR, we can directly address the root cause of the disease at the DNA level. You’re actually going to that one exact site in the genome and putting in the correct letter.

We’ve tested CRISPR in mice that have been engineered with the human gene for PKU. Their phenylalanine levels went from sky-high to stone-cold normal. We have followed those mice for more than a year now, and they’re still normal.