The Promise of One and Done CRISPR-Based Lipid Lowering

 I’ve yet to have a clinic day that doesn’t involve a discussion about cholesterol. As a trainee in general cardiology with an interest in prevention, the benefit of lowering cholesterol is not lost on me. But one of the biggest struggles we face is compliance with a lifetime of daily pills that may bring side effects. 

That’s why I was excited to read about a gene editing therapy that offers the potential for a one-time, durable reduction in both LDL cholesterol and triglycerides. Could the landscape of lipid management be on the verge of a profound shift? 

One-and-Done Lipid Lowering

Results from a phase 1, first-in-human trial of a CRISPR-Cas9 gene editing therapy were presented at the American Heart Association Scientific Sessions and published this past November in The New England Journal of Medicine. 

The therapy, which targets ANGPTL3, a gene shown to regulate LDL and triglyceride metabolism, was given as a single intravenous infusion to patients with elevated lipids despite standard therapies. 

The results were striking. The patients had a dose-dependent reduction of up to nearly 50% for LDL-C, and nearly 55% for triglycerides. And while there were no serious adverse effects related to the therapy in the initial data, it is important to recognize that long-term follow-up is still ongoing. 

We have come far from landmark trials such as 4S and CARE, which saw statins reshape cardiovascular prevention. PCSK9 inhibitors pushed LDL-C levels to places we once thought impossible. These monoclonal antibodies that target a key receptor involved in LDL clearance also showed meaningful decreases in cardiovascular events in trials such as FOURIER and ODYSSEY-OUTCOMES, reinforcing the principle that “ lower is better.” Inclisiran brought the promise of twice-yearly dosing. 

What has not changed throughout this evolution is the duration of therapy — lifelong. This relies on our patients’ adherence, lab monitoring, and continued follow-up visits. 

In early 2025, I was lucky enough to cover the story of Baby KJ, who was born with a rare, life-threatening metabolic disorder. A bespoke CRISPR therapy corrected a specific mutation and allowed the infant to metabolize protein normally and thrive. I remember thinking that CRISPR could revolutionize the management of rare diseases. But now I wonder if its real promise is for the millions of Americans affected by common, long-standing medical conditions such as atherosclerotic cardiovascular disease (ASCVD). 

Potential Candidates for Gene Editing

I can think of three patient archetypes who repeatedly re-enter care, shaped by the same systemic barriers for whom a one-and-done therapy could be life-changing: 

1. The patient with familial hypercholesterolemia on maximal therapy — high-intensity statins, ezetimibe, and even a PCSK9 inhibitor — who is still not at goal.
2. The patient whose statin therapy is limited by debilitating side effects. I am no stranger to this archetype — my own mom falls into this category. Maximal therapy is nearly impossible, and we often find ourselves settling for every-other-day dosing.
3. The patient that others define as noncompliant, but whom I like to think of as having inconsistent adherence. Life is complicated. There are many reasons that patients may not be able to take their medications, including financial stress, misinformation, or distrust of the healthcare system.

However, for someone with a chronic condition such as ASCVD who already has effective, safe, and well-established treatments, the risk/benefit calculation is different than for Baby KJ. He had few treatment options for his rare disease, and thus the potential of long-term risks — CRISPR edits are permanent — was worth it for the benefit of survival. 

One significant theoretical risk is an unintended cut somewhere else in the genome that leads to abnormal cell proliferation or oncogene activation. Immune reactions and delivery-related toxicities particularly related to the liver are other considerations. 

For a young patient with familial hypercholesterolemia, which can be life-threatening, the risk may be worth it. 

And that assumes there is a benefit in terms of clinical outcomes. The phase 1 study was designed to assess early safety only. While we know the therapy reduces LDL-C and triglycerides, we don’t yet know whether this will lead to decreased cardiovascular mortality. 

We have seen trials that move biomarkers without any mortality benefit, such as AIMHIGH, where niacin increased HDL-C and lowered triglycerides but did not reduce the rate of major cardiovascular events. ACCELERATE was another, where the CETP inhibitor evacetrapib led to large increases in HDL-C and significant LDL-C lowering without a reduction in major cardiovascular events. 

Encouragingly, the CRISPR approach is supported by human genetics: people with naturally occurring loss-of-function mutations that affect ANGPTL3 were shown to have lower rates of cardiovascular disease. 

As we await further research to help understand long-term safety and optimal delivery, I remain excited by the possibility that a single infusion could eliminate the need for life-long lipid-lowering therapy for at least some of my patients.

Keerthana R. Pakanati, MD, is the Chief Cardiovascular Fellow at Virginia Mason Franciscan Health and host of The Heart of Prevention podcast with the American Society for Preventive Cardiology. She is passionate about preventing cardiovascular disease, caring for and educating women about their cardiovascular risk, addressing cardiovascular disparities in South Asian populations, and using media to combat medical misinformation. The opinions expressed in this article do not necessarily represent those of the Virginia Mason Franciscan Health System. 

https://www.medscape.com/viewarticle/promise-one-and-done-crispr-based-lipid-lowering-2026a100041q