How CRISPR Gene Editing Works to Lower Cholesterol

The therapy targets the ANGPTL3 gene. Scientists have observed that naturally occurring mutations in this gene are associated with remarkably low cholesterol and triglyceride levels, and a reduced risk of heart disease, without apparent negative side effects. The strategy isn’t to introduce a new gene, but to effectively “switch off” the ANGPTL3 gene in the liver, where cholesterol is primarily produced.

The CRISPR infusion delivers genetic instructions, packaged within a fatty particle, directly to liver cells. These instructions contain molecular “scissors” that precisely cut the ANGPTL3 gene, rendering it non-functional. Researchers confirmed the gene alteration by measuring reduced levels of the ANGPTL3 protein in the participants’ blood. “We confirmed there was less ANGPTL3 protein by knocking out the gene,” explains Sam Kulkarni, CEO of CRISPR Therapeutics. “And it was in a nicely dose-dependent fashion—the higher the dose went, the lower the levels of ANGPTL3 we were seeing.”

Beyond Statins: The Advantages of a One-Time Treatment

Current cholesterol management often relies on daily statin medication. However, adherence is a significant challenge, with roughly half of patients discontinuing statin therapy within a year due to side effects or simply forgetting to take their pills. Other potent treatments, like PCSK9 inhibitors, require regular injections, presenting similar compliance hurdles. Furthermore, PCSK9 inhibitors primarily address cholesterol, while the ANGPTL3 gene editing approach tackles both cholesterol and triglycerides.

Animal studies conducted by CRISPR Therapeutics have demonstrated sustained lipid control for up to two years in monkeys treated with this gene editing technique. Human participants in the current study maintained lower lipid levels for at least six months, with long-term follow-up planned. The FDA typically recommends 15 years of monitoring for gene-editing therapies.

Did You Know? Mutations that naturally lower ANGPTL3 levels are associated with a significantly reduced risk of heart disease, suggesting a powerful genetic link between this gene and cardiovascular health.

Navigating the Risks of Gene Editing

While CRISPR technology holds immense promise, it’s not without potential risks. A previous trial by Intellia Therapeutics, investigating a CRISPR treatment for a rare heart condition, was halted due to instances of severe liver toxicity. However, Kulkarni emphasizes that CRISPR approaches vary significantly between companies. “We have made improvements in all components of our CRISPR therapy,” he states. “And we have been absolutely thorough in making sure that there was no off-tissue editing and all of the editing happened in the liver and nowhere else, and that even in the liver, that we weren’t getting an edit where we shouldn’t.”

One participant in the Cleveland Clinic trial sadly passed away six months after receiving the therapy, but investigators believe the death was unrelated to the treatment, attributing it to pre-existing advanced atherosclerotic disease. Dr. Nissen stresses the need for larger studies to confirm these promising initial results.

Could a future where a single treatment provides lifelong protection against heart disease be within reach? What impact would this have on the healthcare system and the lives of millions at risk?

CRISPR Therapeutics is preparing to initiate Phase 2 trials with a larger patient cohort, initially focusing on individuals who haven’t responded to conventional lipid-lowering therapies. Eventually, the company envisions expanding the therapy’s application to preventative care, offering a proactive solution for those at high risk of developing heart disease. “If you ask me where the world is 20 years from now, I see someone at high risk of heart disease who in their 30s has this gene-editing therapy so they don’t get heart disease in the future,” Kulkarni predicts. “They won’t have to wait until they are 50 and have a heart attack to get this treatment. In some ways, cutting-edge CRISPR should actually be the first line of defense.”

Dr. Nissen echoes this optimism, stating, “I can’t hold back my excitement over the ability to fix this gene and change lipids permanently. There are a lot of people out there we are just not able to fully treat. If we can do this once, then people will potentially have lifelong benefits.”

Further research and rigorous clinical trials are essential, but this initial study represents a monumental step forward in the fight against heart disease, offering a potential paradigm shift in how we approach cholesterol management.

Frequently Asked Questions About Gene Therapy for Cholesterol

• What is gene therapy for cholesterol? Gene therapy for cholesterol aims to permanently lower cholesterol levels by editing the ANGPTL3 gene in the liver, effectively “switching it off” to reduce cholesterol and triglyceride production.
• How effective is this CRISPR-based treatment? In the initial Phase 1 trial, participants receiving the highest dose experienced a 50% decrease in LDL cholesterol and a 55% drop in triglycerides after six months.
• Is CRISPR gene editing safe? While CRISPR technology holds immense promise, potential risks exist, such as off-target editing and immune responses. Researchers are actively working to minimize these risks and ensure the safety of these therapies.
• Who is the ideal candidate for this gene therapy? Currently, the therapy is being investigated for individuals with high cholesterol and triglycerides who haven’t responded to conventional treatments like statins. Future studies may explore its use in preventative care.
• How long do the effects of this gene therapy last? Animal studies suggest effects can last for years. Human participants have maintained lower lipid levels for at least six months, with long-term follow-up ongoing.
• What are the alternatives to gene therapy for managing high cholesterol? Common alternatives include lifestyle modifications (diet and exercise), statin medications, PCSK9 inhibitors (injections), and other cholesterol-lowering drugs.