Lowering cholesterol is one of the most effective ways to reduce your risk of heart disease, and it may soon be possible to have a single gene therapy that will keep your cholesterol and triglycerides low throughout your life.
That's the hope of a small new study led by Dr. Luke Laffin, a preventative cardiologist in Cleveland Clinic's Division of Cardiovascular Medicine, and senior investigator Dr. Steven Nissen, chair of Cleveland Clinic's Department of Cardiovascular Medicine. During the study, 15 people received innovative gene therapy. All patients had high cholesterol, triglycerides, or both, despite treatment with currently available medications, including statins. They received a single dose of CRISPR-based gene editing therapy developed by CRISPR Therapeutics, a company that already has an approved CRISPR therapy for treat sickle cell anemia and shape beta thalassemia. Participants received varying doses of the CRISPR therapy as the early phase 1 study was designed to first assess whether gene editing was safe and provide clues about its potential effectiveness.
Those who received the highest dose had levels of LDL, or bad cholesterol, which can contribute to heart disease, dropped by 50% compared with when they started the study, and triglyceride levels dropped by 55% after six months.
“I think this is a very big deal,” Nissen says. “This is the first time anyone has edited a gene associated with cholesterol metabolism and published the results in a peer-reviewed journal. And the results are quite impressive.”
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The treatment targets the ANGPTL3 gene, which scientists previously found mutated in people with low cholesterol and triglyceride levels; this type of mutation appears to reduce rates of cardiovascular disease without being associated with other health problems. The researchers suggest that in people who do not have the mutation, disrupting the gene using CRISPR by cutting it renders it nonfunctional, potentially leading to lower cholesterol and triglyceride levels.
That's what the Cleveland team saw in the first patients to receive this therapy. The CRISPR infusion included a package of genetic instructions embedded in a fat particle that contained instructions to find liver cells where cholesterol is produced. Inside the particle was a set of molecular scissors with special genetic instructions for cutting the ANGPTL3 gene.
By measuring the level of the protein produced by this gene in the blood, the researchers confirmed that the gene change was doing its job. “We have confirmed that ANGPTL3 has decreased. [protein] knocking out a gene,” says Sam KulkarniCEO of CRISPR Therapeutics, which sponsored the study. “And it was dose dependent: the higher the dose, the lower the ANGPTL3 levels that we observed.”
The research team sees several potential advantages of CRISPR-based therapies over current treatments. For example, many people with high cholesterol rely on statins, but they have to take a pill every day. Research has shown that about half of people who start statin therapy stop after a year due to side effects and difficulty adhering to treatment. A more effective way to combat cholesterol involves another gene involved in cholesterol metabolism, PCSK9. The PCSK9 protein destroys LDL receptors present in cells, 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 affects cholesterol, while ANGPTL3 reduces both LDL and triglycerides.
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Animal studies conducted by CRISPR Therapeutics show that gene-edited monkeys had low cholesterol and triglyceride levels for two years; An ongoing human study has shown that people are able to maintain lipid control for up to six months, and the company plans to follow them long term. (The FDA recommends, but does not require, 15 years of surveillance for gene editing techniques, including those using CRISPR.)
CRISPR has enormous potential to provide one-shot treatments for gene-driven diseases, but this potential also comes with risks. Intellia Therapeutics, which was studying a CRISPR treatment for a rare genetic heart disease, stopped the study after participants developed severe liver toxicity.
Kulkarni says not all CRISPR approaches are created equal, with each company developing its own gene delivery and editing package. “We have improved all the components of our CRISPR therapy,” he says. “And we were absolutely careful to make sure that there was no extra-tissue editing, and that all the editing was happening in the liver and nowhere else, and that even in the liver we weren't getting editing where we shouldn't.”
One participant in the current study died six months after receiving therapy, but Nissen says the patient had advanced atherosclerotic disease and “none of the participants think that [the death] had something to do with therapy. However, vigilance is required here. These are promising results, but [the therapy] needs to be studied in a larger patient population.”
Read more: How to Keep Your Heart Healthy in Your 20s, 30s, 40s and Beyond
Both 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. Although the current study focuses only on those who cannot control their lipids, one-time gene editing could potentially be extended to more people to help them control their cholesterol and triglyceride levels and even protect them from cardiovascular disease. “If we have someone in their 30s or 40s with a strong family history of coronary artery disease, we know that these patients may not be taking preventative treatments like statins, because we know that 50% of patients stop taking statins,” Laffin says. “If there was a one-time treatment that could lower cholesterol levels throughout your life, that would be a dream.”
Kulkarni says the company plans to move into the next phase of studies with a larger group of patients, focusing primarily on those who have not responded to current lipid-lowering therapy, but ultimately studying the therapy as a way to prevent cardiovascular disease in people who may be at higher risk but do not yet have any symptoms. “If you ask me where the world will be in 20 years, I will see a person at high risk of heart disease who in his 30s undergoes gene-editing therapy so that he will not have heart disease in the future,” he says. “They won't have to wait until they're 50 and have a heart attack to get this treatment. In some ways, advanced CRISPR should really be the first line of defense.”
If the results of the next phase of research are equally encouraging, then gene-editing therapies to control lipids may not be far off. “I can’t help but be excited about the possibility of correcting this gene and changing lipids forever,” says Nissen. “There are a lot of people that we just can't completely cure. If we can do it once, people could potentially benefit for life.”
