Can a One-Time Gene Therapy Lower Cholesterol?

Lowering cholesterol is one of the most effective ways to reduce your risk of heart disease, and it may soon be possible to benefit from a unique gene therapy to keep cholesterol and triglyceride levels low throughout your life.

That’s the hope of a small new study led by Dr. Luke Laffin, a preventive cardiologist in the Cleveland Clinic’s department of cardiovascular medicine, and principal investigator Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. During the trial, 15 people received the innovative gene therapy. All patients had high cholesterol, high triglycerides, or both, despite being treated with currently available medications, including statins. They received a one-time infusion of a CRISPR-based gene editing therapy designed by CRISPR Therapeutics, a company that already has an approved CRISPR therapy to treat sickle cell disease and a form of beta thalassemia. Participants received different doses of the CRISPR therapy, since the first phase 1 trial was designed primarily to assess whether gene editing was safe and provide guidance on its potential effectiveness.

Those who received the highest dose saw a 50% drop in LDL, or bad cholesterol that can contribute to heart disease, from the start of the study, and a 55% drop in triglyceride levels after six months.

“In my opinion, this is a very big deal,” says Nissen. “This is the first time that someone has modified a gene linked to cholesterol metabolism and published their results in a peer-reviewed journal. And the results are quite spectacular.”

Learn more: How to lower your cholesterol naturally

The treatment targets a gene called ANGPTL3, which scientists have previously found to be mutated in people with low cholesterol and triglyceride levels; this type of mutation appears to reduce rates of heart disease, without being linked to other health problems. In people who do not have the mutation, researchers believe that disrupting this gene with CRISPR by cutting it renders it nonfunctional, which could lead to lower cholesterol and triglyceride levels.

This is what the Cleveland team saw in the first patients to receive the therapy. The CRISPR infusion included a set of genetic instructions, encased in a fat particle, containing instructions for finding the liver cells where cholesterol is made. Inside the particle was a set of molecular scissors containing specific genetic instructions for cutting the ANGPTL3 gene.

By measuring the levels of protein produced by the gene in the blood, the researchers verified that the gene alteration was doing its job. “We confirmed that there was less ANGPTL3 [protein] by knocking out the gene,” says Sam Kulkarni, CEO of CRISPR Therapeutics, which sponsored the study. “And it was in a very dose-dependent way: the higher the dose, the lower the ANGPTL3 levels we observed.”

The research team sees several potential advantages in CRISPR-based therapy over current treatments. Many people with high cholesterol, for example, use statins but must take a pill every day. Studies have shown that about half of people who start statin therapy stop after a year due to side effects and difficulty with compliance. A more effective way to fight cholesterol involves another gene involved in cholesterol metabolism, PCSK9. The PCSK9 protein degrades the receptors that cells have for LDL, which is important for removing LDL from the blood; Inhibiting the protein allows more cells to retain the receptors and helps lower LDL levels. There are several approved treatments that inhibit PCSK9 activity, but they require regular injections and compliance can still be a challenge. Additionally, PCSK9 only processes cholesterol, while ANGPTL3 reduces both LDL and triglycerides.

Learn more: The obscure genetic cholesterol that may impact your heart health

Animal studies conducted by CRISPR Therapeutics show that monkeys treated with gene editing kept their cholesterol and triglyceride levels low for two years; the current human study showed that people were able to maintain control of their lipids for up to six months, and the company plans to follow them long term. (The FDA recommends, but does not require, a 15-year follow-up for gene-editing therapies, including those involving CRISPR.)

CRISPR has enormous power to provide timely treatments for genetically-based diseases, but this potential also carries risks. Intellia Therapeutics, which was studying a CRISPR treatment for a rare genetic heart disease, stopped its trial after participants developed severe liver toxicity.

Kulkarni says not all CRISPR approaches are the same, with each company developing its own gene delivery and editing package. “We have improved every component of our CRISPR therapy,” he says. “And we made sure that there were no changes outside the tissue and that all the changes were happening in the liver and nowhere else, and that even in the liver we weren’t getting changes where we shouldn’t.”

One participant in the current trial died six months after receiving the treatment, but Nissen says the patient had advanced atherosclerotic disease and “no one involved thinks [the death] had nothing to do with therapy. However, vigilance is required here. These are promising results, but [the therapy] should be studied in a larger patient population.

Learn more: How to Keep Your Heart Healthy in Your 20s, 30s, 40s, and Beyond

Kulkarni and the doctors involved in the study believe that a broader population of people with high cholesterol and triglycerides could one day benefit from CRISPR therapy. While the current study focused only on those who couldn’t control their lipids, one-time gene editing could potentially be extended to more people to help them control their cholesterol and triglycerides and even protect them from cardiac events. “If we have someone in their 30s or 40s with a serious family history of coronary heart disease, we know that those patients may not be taking preventative treatments like statins, since we know that 50% of them stop taking statins,” Laffin says. “If there was a single treatment that could lower their cholesterol levels throughout their lives, it would be a dream.”