The World's Deadliest Disease Has a Cholesterol Problem
Cardiovascular disease kills more people than any other cause on Earth. According to the World Health Organization, an estimated 17.9 million people die from cardiovascular conditions every year, accounting for roughly 32% of all global deaths. In the United States alone, heart disease claims approximately 700,000 lives annually, making it the leading cause of death for both men and women across most racial and ethnic groups.
At the root of much of this mortality sits a waxy, fat-like molecule: cholesterol. Specifically, low-density lipoprotein cholesterol — LDL-C, often called "bad cholesterol" — builds up in artery walls over decades, forming plaques that narrow blood vessels and eventually trigger heart attacks and strokes. The relationship between LDL-C and cardiovascular risk is one of the most well-established findings in all of medicine. Every 1 mmol/L (roughly 39 mg/dL) reduction in LDL-C translates to about a 22% reduction in major cardiovascular events.
The problem is not that we lack treatments. The problem is that the treatments we have require a lifetime of adherence — and most patients fall short.
The Current Arsenal: Statins, PCSK9 Inhibitors, and Inclisiran
Statins have been the backbone of cholesterol management since lovastatin was approved in 1987. Drugs like atorvastatin (Lipitor) and rosuvastatin (Crestor) work by inhibiting HMG-CoA reductase, an enzyme the liver uses to produce cholesterol. They are cheap, well-studied, and effective, reducing LDL-C by 30-50% on average. By some estimates, statins have saved millions of lives over the past four decades.
But statins have a compliance problem. Studies consistently show that roughly half of patients prescribed a statin stop taking it within a year. Side effects — real or perceived muscle pain being the most common complaint — drive some patients away. Others simply forget, lose motivation, or cannot afford ongoing prescriptions. The result is a vast population of people who know their cholesterol is too high but are not consistently treating it.
PCSK9 inhibitors arrived in 2015 as a powerful alternative. PCSK9 is a protein that degrades LDL receptors on liver cells. When PCSK9 is blocked, more LDL receptors survive on the cell surface, pulling more LDL-C out of the bloodstream. Monoclonal antibody drugs like evolocumab (Repatha) and alirocumab (Praluent) can slash LDL-C by 50-60% on top of statin therapy, achieving levels previously thought impossible. But these drugs require injections every two to four weeks and originally carried price tags exceeding $14,000 per year, though costs have since come down significantly.
Inclisiran (Leqvio), approved by the FDA in 2021, represented a step toward longer-lasting treatment. This small interfering RNA (siRNA) drug silences the gene that produces PCSK9 in the liver, requiring only two injections per year after an initial loading dose. It achieves LDL-C reductions of around 50%. Inclisiran is a genuine advance in convenience, but it is still a chronic therapy — patients need those twice-yearly injections for the rest of their lives, and if they stop, their cholesterol rebounds.
Each generation of cholesterol drug has been more potent and more convenient than the last. But they all share a fundamental limitation: they are temporary. Stop taking them, and the underlying biology reasserts itself. What if, instead of fighting the body's cholesterol-producing machinery with repeated doses of medication, you could simply edit the genetic instructions that drive cholesterol production in the first place?
The Gene Editing Approach: Rewrite the Liver, Once
The concept is elegant in its simplicity. Several genes in the liver regulate how much cholesterol and other lipids circulate in the blood. If you could permanently alter one of those genes — disabling it in a targeted, controlled way — you could achieve a lasting reduction in LDL-C or other atherogenic lipids with a single treatment.
This is not science fiction. Nature has already run the experiment. Researchers have identified people who carry natural loss-of-function mutations in genes like PCSK9 and ANGPTL3. These individuals have dramatically lower cholesterol levels and are remarkably protected against heart disease, often with no apparent health downsides. A famous study published in the New England Journal of Medicine in 2006 found that individuals with loss-of-function PCSK9 mutations had LDL-C levels 28% lower than average and an 88% reduction in coronary heart disease risk.
The therapeutic strategy is to mimic what nature has already proven safe. Using lipid nanoparticles — tiny fat bubbles similar to those used in mRNA COVID-19 vaccines — researchers can deliver gene editing machinery directly to the liver after a simple intravenous infusion. The editing tools make precise changes to the target gene in liver cells, permanently reducing the production of proteins that raise cholesterol.
Two companies have emerged as leaders in this space: Verve Therapeutics, focused on PCSK9, and CRISPR Therapeutics, targeting ANGPTL3 and lipoprotein(a). Their clinical programs tell a story of both remarkable promise and sobering challenges.
Verve Therapeutics: Pioneering PCSK9 Base Editing
Verve Therapeutics, founded in 2018 by cardiologist Sekar Kathiresan, was built on a single bold idea: use base editing to permanently turn off the PCSK9 gene in the liver, achieving lifelong cholesterol reduction with one injection. Kathiresan, who had spent his career studying the genetics of heart disease at the Broad Institute and Massachusetts General Hospital, recognized that the natural human genetics data pointed clearly toward PCSK9 as a safe and effective target.
Verve's approach uses adenine base editing — a technology developed by David Liu at the Broad Institute — delivered via lipid nanoparticles. Unlike traditional CRISPR-Cas9, which cuts both strands of DNA, base editors chemically convert one DNA letter into another without making double-strand breaks. This is a critical distinction: base editing is considered more precise and less likely to cause unintended insertions, deletions, or chromosomal rearrangements.
VERVE-101: First-in-Human, Hard Lessons
VERVE-101 was the company's first clinical candidate, using an adenine base editor to disrupt the PCSK9 gene. In 2022, Verve launched a Phase 1b clinical trial called heart-1 in patients with heterozygous familial hypercholesterolemia (HeFH) — a genetic condition that causes dangerously high cholesterol from birth — and established atherosclerotic cardiovascular disease.
The early data showed proof of concept. Patients treated with VERVE-101 showed reductions in blood PCSK9 protein levels and corresponding decreases in LDL-C. The editing machinery was reaching the liver, making the intended changes, and the biological effect was measurable.
But the trial also delivered a devastating blow. One patient in the study died from a cardiac event five weeks after receiving VERVE-101. While the Data Safety Monitoring Board reviewed the case and the trial was allowed to continue, the incident cast a long shadow. The patient had severe pre-existing cardiovascular disease — the very population the drug was intended to treat — but the death underscored the extraordinarily high safety bar that any one-time, irreversible treatment must clear.
Additional safety signals emerged around transient elevations in liver enzymes and reductions in platelet counts, effects likely related to the lipid nanoparticle delivery system rather than the base editing itself. These were manageable but added to the cautious picture.
In late 2023, Verve made the strategic decision to deprioritize VERVE-101 and shift its focus to a next-generation program. The first-generation candidate had served its purpose as a trailblazer, but the company recognized that a better version was needed to meet the safety and efficacy requirements for a transformative cardiovascular therapy.
VERVE-102: Next Generation, Stronger Results
VERVE-102 represents Verve's refined approach. It uses an improved lipid nanoparticle delivery system and an optimized base editing construct, still targeting PCSK9 but with changes designed to enhance potency and reduce off-target effects and delivery-related side effects.
The early clinical data from VERVE-102 have been markedly more encouraging. In the Phase 1b heart-2 trial, patients with HeFH treated with VERVE-102 achieved LDL-C reductions of 53-69%, depending on the dose — numbers that rival or exceed what PCSK9 monoclonal antibodies and inclisiran achieve, but from a single infusion. Critically, VERVE-102 has not shown the serious adverse events that complicated VERVE-101. No treatment-related serious adverse events have been reported in the trial as of the most recent data cutoff.
The magnitude of LDL-C reduction is particularly notable. A 53-69% decrease in LDL-C, if durable, would translate into a massive reduction in cardiovascular risk over a patient's lifetime. For someone diagnosed with familial hypercholesterolemia in their thirties, a permanent reduction of that magnitude could mean decades of additional protection against heart attacks and strokes — protection that does not depend on remembering to take a pill or show up for an injection.
Durability remains the key open question. The clinical follow-up so far is measured in months. The theoretical expectation, based on the mechanism of base editing and the slow turnover rate of hepatocytes (liver cells have a half-life measured in years), is that the effect should last for many years and possibly a lifetime. But proving lifelong durability will, by definition, require years of follow-up data.
Eli Lilly Bets $1.3 Billion on the Future
In late 2025, pharmaceutical giant Eli Lilly announced an agreement to acquire Verve Therapeutics for approximately $1.3 billion. The acquisition signaled something important: one of the world's largest and most sophisticated drug companies had looked at the gene editing approach to cardiovascular disease and decided it was worth a major bet.
Eli Lilly's interest was not purely speculative. The company has a deep cardiovascular and metabolic disease portfolio and recognized that a one-time gene editing treatment could be a paradigm-shifting product in a market currently served by chronic therapies. The acquisition also gave Lilly access to Verve's broader platform of liver-directed gene editing, which could theoretically be applied to targets beyond PCSK9.
The deal was also a vote of confidence in the broader concept of in vivo gene editing — the idea that you can safely and effectively edit genes inside a living person's body, without removing cells, modifying them in a lab, and putting them back. If Verve's approach works at scale, the implications extend far beyond cholesterol.
CRISPR Therapeutics: ANGPTL3 and the NEJM Milestone
While Verve focused on PCSK9, CRISPR Therapeutics — the company co-founded by Emmanuelle Charpentier, who shared the 2020 Nobel Prize for the discovery of CRISPR — took aim at a different target: ANGPTL3.
ANGPTL3 (angiopoietin-like 3) is a protein produced by the liver that inhibits enzymes responsible for breaking down triglycerides and other lipids. People with natural loss-of-function mutations in ANGPTL3 have very low levels of LDL-C, triglycerides, and HDL-C, and they are strongly protected against coronary artery disease. Unlike PCSK9, which primarily affects LDL-C, knocking out ANGPTL3 lowers multiple atherogenic lipid fractions simultaneously, making it an appealing target for patients with complex lipid disorders.
CTX310: Proof of Concept in Humans
CTX310 is CRISPR Therapeutics' in vivo gene editing program targeting ANGPTL3. It uses a CRISPR-Cas9-based approach delivered via lipid nanoparticles to knock out the ANGPTL3 gene in liver cells. The company initiated a Phase 1 clinical trial in patients with elevated lipid levels.
The results, published in the New England Journal of Medicine, marked a landmark for the field. CTX310 demonstrated substantial reductions in ANGPTL3 protein levels, LDL-C, and triglycerides in treated patients. The data confirmed that a single dose of in vivo CRISPR gene editing could achieve meaningful and sustained lipid lowering in humans.
Publication in the NEJM was significant not just for the data itself but for what it represented: peer-reviewed validation in the world's most prestigious medical journal that in vivo gene editing for a common chronic disease was feasible, effective, and — based on early data — reasonably safe. The safety profile showed transient effects associated with the lipid nanoparticle delivery, including mild elevations in liver enzymes, but no serious safety signals that would halt the program.
The CTX310 data also validated ANGPTL3 as a therapeutic target and demonstrated that CRISPR-Cas9 (as opposed to base editing) could be used effectively for liver-directed gene editing. This is worth noting because base editing and CRISPR-Cas9 have different risk profiles: CRISPR-Cas9 creates double-strand breaks, which carry a theoretical risk of large deletions or chromosomal rearrangements, while base editing avoids these but has its own potential for bystander edits. The CTX310 results suggested that, at least in the liver, CRISPR-Cas9 delivered via lipid nanoparticles could achieve clean, effective gene knockout.
CTX340: Going After Lipoprotein(a)
CRISPR Therapeutics is not stopping at ANGPTL3. The company's next cardiovascular target is lipoprotein(a) — often written as Lp(a) — one of the most stubborn and underappreciated risk factors in cardiovascular medicine.
Lp(a) is a genetically determined lipoprotein that is structurally similar to LDL but carries an additional protein called apolipoprotein(a). Elevated Lp(a) levels affect an estimated 20% of the global population and are associated with a significantly increased risk of heart attack, stroke, and aortic valve disease. Unlike LDL-C, Lp(a) levels are largely unaffected by diet, exercise, or statins. Until recently, there was essentially no effective pharmacological treatment.
Several pharmaceutical companies are developing RNA-based therapies to lower Lp(a), including Novartis (pelacarsen, now muvalaplin) and Amgen (olpasiran). These drugs have shown dramatic Lp(a) reductions in clinical trials. But like all RNA-based approaches, they require ongoing dosing — monthly or quarterly injections for life.
CTX340 aims to permanently reduce Lp(a) by editing the gene responsible for producing apolipoprotein(a) in the liver. CRISPR Therapeutics has announced plans to file an Investigational New Drug (IND) application with the FDA in the first half of 2026, which would allow the company to begin clinical trials.
If CTX340 works, it would offer something no current therapy can: a one-time treatment that permanently lowers a cardiovascular risk factor for which 20% of the human population is genetically predisposed. For patients with extremely high Lp(a) levels who face elevated cardiovascular risk regardless of how well they control their LDL-C, this could be genuinely life-changing.
The One-Time Cure vs. the Daily Pill
The therapeutic programs from Verve and CRISPR Therapeutics represent something more than incremental improvements in lipid management. They embody a fundamental shift in how we think about treating chronic disease.
The current model of cardiovascular medicine is based on chronic intervention. You diagnose high cholesterol, prescribe a statin, and the patient takes it every day for the rest of their life. If the statin is not enough, you add ezetimibe. If that is not enough, you add a PCSK9 inhibitor. Each layer adds cost, complexity, and another opportunity for the patient to fall out of compliance. The entire system is built around the assumption that the underlying biology cannot be changed — only managed.
Gene editing challenges that assumption directly. If you can make a single, permanent change to the genetic instructions in a patient's liver cells, you have not just treated the disease — you have altered the patient's biology to be inherently protected against it. The patient does not need to remember anything, refill any prescriptions, or return for any follow-up injections. They simply have lower cholesterol, the same way that people born with natural loss-of-function mutations have lower cholesterol.
This paradigm shift has enormous implications for global health equity. In wealthy countries, the challenge of cholesterol management is largely one of compliance and cost optimization. But in low- and middle-income countries, where cardiovascular disease is responsible for the majority of premature deaths, access to chronic medications is a far more fundamental barrier. Many patients in sub-Saharan Africa, South Asia, and Southeast Asia have no access to statins at all, let alone PCSK9 inhibitors. A one-time treatment that permanently reduces cardiovascular risk could, in theory, be deployed through the same public health infrastructure that delivers vaccines — reaching populations that the current chronic medication model simply cannot serve.
Of course, this vision depends on cost. The first generation of gene editing treatments will almost certainly carry price tags in the hundreds of thousands of dollars, comparable to other gene therapies. But the economics of a one-time treatment are fundamentally different from those of a chronic therapy. If a single infusion replaces 40 years of PCSK9 inhibitor prescriptions, the lifetime cost calculus may favor the gene editing approach even at a high upfront price. And as manufacturing scales and competition increases, costs will likely come down — just as they have for every other biotechnology platform.
The Challenges: Irreversibility, Safety, and the Bar for Chronic Disease
For all its promise, the gene editing approach to cardiovascular disease faces challenges that are qualitatively different from those of traditional drug development.
Irreversibility is a feature and a bug. The permanence of gene editing is the entire point — that is what makes a one-time treatment possible. But it also means that if something goes wrong, there is no stopping the drug. You cannot discontinue a gene edit the way you can stop taking a pill. If an unforeseen long-term effect emerges five or ten years after treatment, there is no recall, no dose adjustment, no washout period. The edit is part of the patient's genome for life.
This is why the safety bar for gene editing in cardiovascular disease is so much higher than for gene editing in fatal genetic diseases. When CRISPR Therapeutics won FDA approval for Casgevy, its gene editing treatment for sickle cell disease, the risk-benefit calculation was relatively straightforward: sickle cell disease causes severe, lifelong suffering and early death, so even a treatment with significant side effects can be justified. But cardiovascular disease caused by high cholesterol is managed — imperfectly, but managed — by existing drugs. Regulators and physicians will rightly demand an exceptional safety profile before approving an irreversible treatment for a condition that patients can live with, even if suboptimally, using current therapies.
Off-target editing remains a concern, though the risk profile varies by technology. Base editors can make "bystander" edits at nearby positions within their editing window, and CRISPR-Cas9 can occasionally cut at sites that resemble but are not identical to the intended target. Both Verve and CRISPR Therapeutics have invested heavily in characterizing their off-target profiles, and the clinical data to date have not revealed concerning off-target effects. But long-term surveillance will be essential.
Delivery-related side effects are a practical challenge. The lipid nanoparticle delivery systems used by both companies can cause transient inflammatory responses, liver enzyme elevations, and reductions in platelet counts. These effects are generally mild and self-limiting, but they add to the overall risk profile and may limit the doses that can be safely administered. Improving LNP technology to reduce immunogenicity while maintaining efficient liver targeting is an active area of research across the industry.
Durability in clinical practice is still unproven. The theoretical basis for lifelong durability is strong — edited hepatocytes should pass their modified genomes to daughter cells when they divide — but liver biology is complex. Ongoing clinical trials will need to demonstrate that the cholesterol-lowering effect persists for years, not just months. If the effect wanes over time, the value proposition of a one-time treatment erodes significantly.
Equity and access present a paradox. Gene editing treatments could, in principle, democratize cardiovascular prevention by replacing chronic medication regimens with single doses. But if the treatments are priced at hundreds of thousands of dollars and require sophisticated clinical infrastructure to administer, they may initially exacerbate rather than reduce health disparities. The path from breakthrough therapy to global public health tool is long and uncertain.
What Comes Next
The next two to three years will be pivotal for gene editing in cardiovascular disease. Verve (now under the Eli Lilly umbrella) will continue to advance VERVE-102 through clinical trials, with longer-term durability and safety data expected to shape the program's trajectory. CRISPR Therapeutics will push CTX310 toward later-stage trials while initiating the first human studies of CTX340 for Lp(a). Other companies, including Intellia Therapeutics and several smaller biotechs, are developing their own liver-directed gene editing programs for cardiovascular targets.
The regulatory path is also taking shape. The FDA has shown a willingness to engage constructively with gene editing developers, and the agency's experience with approved gene therapies for other conditions provides a framework — though not a template — for evaluating cardiovascular gene editing treatments. The key question regulators will grapple with is how to balance the immense potential benefit of permanent cholesterol reduction against the theoretical risks of irreversible gene editing in a large, relatively healthy patient population.
If the clinical data continue to mature favorably — if VERVE-102 and CTX310 demonstrate durable LDL-C reductions with clean safety profiles over multiple years of follow-up — the first gene editing treatment for cardiovascular disease could reach the market by the end of this decade. That would mark a turning point not just for cardiology but for the entire concept of genetic medicine: the moment when gene editing moved from treating rare, devastating diseases to preventing the world's most common killer.
The vision that Sekar Kathiresan articulated when he founded Verve — a single injection that permanently protects against heart disease — may be closer to reality than skeptics once believed. Not because the challenges have been solved, but because the science is proving, patient by patient, dose by dose, that the human liver can be safely and effectively edited to lower cholesterol. The rest is execution, time, and the willingness to believe that medicine's oldest enemy might finally have met its match.
Sources
- World Health Organization. "Cardiovascular Diseases (CVDs)." WHO Fact Sheet, 2024.
- Cholesterol Treatment Trialists' Collaboration. "Efficacy and Safety of More Intensive Lowering of LDL Cholesterol." The Lancet, 2010.
- Cohen, J.C., Boerwinkle, E., Mosley, T.H., Hobbs, H.H. "Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease." New England Journal of Medicine, 2006.
- Musunuru, K., et al. "In Vivo CRISPR Base Editing of PCSK9 Durably Lowers Cholesterol in Primates." Nature, 2021.
- Verve Therapeutics. "Verve Therapeutics Presents Updated Clinical Data from VERVE-102 Phase 1b heart-2 Trial." Press Release, 2025.
- Verve Therapeutics. "Verve Therapeutics Reports Clinical Data from VERVE-101 heart-1 Trial." Press Release, 2023.
- CRISPR Therapeutics. "CRISPR Therapeutics Reports Positive Phase 1 Data for CTX310." Press Release, 2025.
- Belluck, P., Kolata, G. "Gene Editing for Heart Disease Shows Promise in Early Trial." New York Times, 2025.
- Eli Lilly and Company. "Lilly to Acquire Verve Therapeutics." Press Release, 2025.
- Dewey, F.E., et al. "Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease." New England Journal of Medicine, 2017.
- Nordestgaard, B.G., Langsted, A. "Lipoprotein(a) as a Cause of Cardiovascular Disease: Insights from Epidemiology, Genetics, and Biology." Journal of Lipid Research, 2020.
- CRISPR Therapeutics. "CRISPR Therapeutics Announces Plans for CTX340 IND Filing." Press Release, 2025.
- Nissen, S.E., et al. "Single Ascending Dose Study of CRISPR-Based In Vivo Gene Editing for Lipid Lowering." New England Journal of Medicine, 2025.
