With a snip of a gene, doctors may one day permanently lower dangerously high cholesterol, possibly removing the need for medication, according to a new pilot study published Saturday in the New England Journal of Medicine, reports BritPanorama.
The study involved a small group of 15 patients suffering from severe disease and was primarily designed to assess the safety of a novel medication delivered via CRISPR-Cas9, a technology that can cut targeted genes to modify their function.
Preliminary results indicated nearly a 50% reduction in low-density lipoprotein (LDL) cholesterol, known as “bad” cholesterol due to its significant role in heart disease, which remains the leading cause of mortality among adults in the United States and globally.
Presented at the American Heart Association Scientific Sessions in New Orleans, the study also highlighted an average 55% reduction in triglycerides, a type of fat in the bloodstream associated with elevated cardiovascular risk.
“We hope this is a permanent solution, where younger people with severe disease can undergo a ‘one and done’ gene therapy and have reduced LDL and triglycerides for the rest of their lives,” stated Dr. Steven Nissen, chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic in Ohio.
He remarked, “That’s a dream come true. If you’d asked me 15 years ago if we could have done something like this, I would have thought you were crazy.”
Currently, cardiologists advocate for patients with existing heart disease or those genetically predisposed to high cholesterol to maintain LDL levels well below 100, which is the current average in the U.S., according to Dr. Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital.
“Evidence suggests that the optimal cholesterol level is between 40 and 50, which is challenging to achieve solely through diet and lifestyle,” Dr. Natarajan, who was not involved in the study, added.
While existing medications can lower LDL cholesterol significantly, some therapeutic options exceeded the effectiveness reported in this early study. “So we’re going to have to wait and see if this treatment works as well as this first study suggests,” he indicated.
Despite its early phase, the findings are compelling because they address the common issue of medication adherence, noted Dr. Ann Marie Navar, a preventive cardiologist at UT Southwestern Medical Center. “In spite of having a lot of available therapies, the majority of people do not have their LDL under control,” she emphasized.
Dr. Navar argued, “If you’re 20 and have extremely high cholesterol, a one-time treatment could be more beneficial than a daily pill or bi-weekly injection for the next 60 years. The potential for this is just enormous.”
A lucky mutation to reduce high cholesterol
This gene-editing approach is inspired by a rare genetic mutation that effectively turns off the ANGPTL3 gene, responsible for regulating LDL and triglyceride levels.
Approximately 1 in 250 individuals in the U.S. have a nonfunctioning ANGPTL3 gene, resulting in lifelong low levels of LDL cholesterol and triglycerides without adverse effects. Such individuals exhibit minimal risk for cardiovascular disease.
“It’s a naturally occurring mutation that provides protection against cardiovascular disease,” Dr. Nissen noted. “With CRISPR technology, we can potentially modify other individuals’ genes to confer this protection.”
Participants were administered varying doses of the CRISPR-based drug through infusion. “The average 55% decrease in triglycerides and nearly 50% in LDL cholesterol occurred at the highest dose,” said Dr. Luke Laffin, the study’s lead author. “This is significant because no current therapies lower both LDL cholesterol and triglycerides simultaneously.”
Notably, there was a slight decrease in HDL (high-density lipoprotein), commonly referred to as “good” cholesterol. However, this drop mirrors what is seen in those with the ANGPTL3 mutation and is not considered harmful.
“The most common disorder in our prevention clinic is mixed hyperlipidemia— patients struggle to manage both LDL and triglycerides. Being able to address both in one treatment is a critical advance,” Dr. Nissen remarked.
Long-term safety profile
In individuals with the natural mutation, the ANGPTL3 gene is inactive in all body cells, whereas this new medication specifically targets the liver, responsible for cholesterol synthesis and triglyceride production.
This localization is encouraging for the drug’s long-term safety, reducing the likelihood of unintended gene editing elsewhere, as emphasized by Dr. Nissen.
Initial treatment-side effects were minimal, primarily localized injection-site irritation. However, one participant developed a spinal disk herniation and another showed an increase in liver enzyme levels—these conditions resolved within two weeks.
Tragically, one participant died six months post-infusion; however, Dr. Nissen clarified that he had severe cardiovascular disease and received the smallest dosage, which “doesn’t do anything.”
“We don’t believe his death impacts the study at all,” he reassured. The FDA is advising ongoing monitored follow-ups for these participants over 15 years to detect any long-term adverse effects.
Plans for Phase 2 clinical trials are underway, to be followed swiftly by Phase 3 trials aimed at assessing the drug’s efficacy on a larger demographic, according to Dr. Nissen.
“We hope to complete all this by the end of next year,” he added, stressing the urgency due to the unmet medical needs of millions unresponsive to existing treatments. “That’s a significant under-treatment issue in the United States.”
Nevertheless, caution is advised as this field is still in its nascent stages, given the historical challenges faced by promising therapies that faced rejection over safety concerns. Dr. Nadar cautioned, “The most vital takeaway is for those on cholesterol-lowering medications to continue their regimen. Data consistently show that the longer LDL cholesterol is kept low, the better the health outcome.”
