When Mechanism Becomes Medicine
Statins, PCSK9, CRISPR, and the Next Wave of Heart Disease Prevention
Introduction
“If your doctor could give you one injection—a CRISPR treatment that actually changed your genes and lowered your numbers, maybe for life—would you do that?” That was the question Ira Flatow posed to listeners in a recent Science Friday episode on statins and the future of cholesterol treatment.[1] It is such a deceptively simple question that it almost sneaks past the magnitude of what it contains. Statins are so familiar now that it is easy to forget they represent one of the great successes of modern medicine. Millions of people take them. They are the current standard of care when LDL cholesterol rises above a certain threshold or when cardiovascular risk becomes impossible to ignore. Yet familiarity can obscure the scale of the achievement. Statins did not emerge because clinicians suddenly decided cholesterol mattered. They emerged because decades of basic science, epidemiology, clinical trials, and risk modeling established a durable truth: lowering LDL cholesterol lowers the risk of heart attack, stroke, and premature death. And now, the story of cholesterol treatment is no longer just the story of statins. It is also the story of PCSK9, of people born with naturally protective variants, of monoclonal antibodies and siRNA, of CRISPR base editing, and of a provocative possibility: that one day some patients may receive a one-time intervention that mimics a favorable genetic lottery they did not inherit. Furthermore, more recent studies are revealing how the physical properties of cholesterol trigger inflammation that is a deeper root cause of negative cardiovascular outcomes. Intrigued? You should be – this story of how mechanism led to medicine then to confirmation, then back to mechanism is fascinating.
How Statins Got Us Here
To understand this story, it helps to begin with the elegance of statins as a treatment. Statins work by blocking the liver’s ability to synthesize cholesterol from scratch. More specifically, statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway of cholesterol biosynthesis. The liver responds by increasing LDL receptor activity, which pulls more LDL particles out of circulation. The result is lower blood LDL cholesterol, and over time, lower exposure of arteries to the particles that help drive atherosclerosis. Michael Brown and Joseph Goldstein at UT Southwestern reported the groundbreaking research that uncovered this basic biology in 1974 and were awarded the Nobel Prize in Physiology and Medicine in 1985 for this work.[2] Almost simultaneously, Japanese biochemist Akira Endo at Sankyo Pharmaceuticals began searching in 1971 for microbial compounds that could inhibit HMG-CoA reductase. In 1976, he isolated mevastatin from Penicillium citrinum mold, the first HMG-CoA reductase inhibitor and the founding molecule of the statin class. Around the same time, Al Alberts and colleagues at Merck independently discovered lovastatin, which became the first commercially approved statin in 1987.[3]
Brown & Goldstein’s mechanistic insight, along with Endo’s proof of the pharmacologic target, became clinically transformative because they was followed by evidence on a scale medicine rarely gets. Large randomized trials and meta-analyses involving hundreds of thousands of patients have shown that statins reduce major coronary events, strokes, and mortality, with risk reduction tracking closely with the magnitude of LDL lowering. [4, 5] The cumulative message across those studies is remarkably consistent: LDL is not merely associated with cardiovascular risk; it is causally implicated in it, and lowering it matters. This matters because cardiovascular disease remains the leading cause of death globally.[1] When statins lower LDL and thereby reduce cardiovascular events, they are not simply improving a lab number. They are intervening in the largest cause of mortality across countries, income levels, and healthcare systems.
At the same time, the statin story has never been as frictionless as guideline language can make it sound. Patients stop taking chronic oral drugs. Some experience real side effects. Many more worry about side effects, and sometimes expectation itself becomes part of the clinical picture. Blinded studies suggest that true statin myopathy is much less common than popular discussion implies, but the adherence problem remains real whether symptoms are pharmacologic, perceptual, or both. Nevertheless, clinical outcomes for statin use are so positive that strategies for increasing statin adherence are the subject of frequent study. [6, 7]. The gap between trial efficacy and real-world persistence matters. A pill that works biologically still fails strategically if a large fraction of patients does not take it long enough to capture lifetime benefit. This is one reason the cholesterol field kept moving. The scientific question was no longer only whether LDL lowering works. It was how to make LDL lowering deeper, more durable, more tolerable, and less dependent on perfect daily adherence.
The PCSK9 Story
If statins proved the LDL hypothesis at scale, PCSK9 sharpened it with unusual precision. PCSK9 is a protein made largely in the liver that affects how many LDL receptors remain available on hepatocytes to clear LDL cholesterol from the bloodstream. When PCSK9 activity is high, more LDL receptors are degraded. Fewer receptors mean less LDL clearance and higher circulating LDL cholesterol.[8] The inverse is what made PCSK9 such an attractive target: turn PCSK9 down, and LDL receptor availability rises, increasing the removal of LDL cholesterol.
What made the story compelling was not just the biology. It was the human genetics. Researchers identified naturally occurring loss-of-function variants in PCSK9 in a subset of people who walk around with lower LDL cholesterol and dramatically lower rates of coronary heart disease.[8] In the Science Friday discussion, Dr. Kiran Musunuru described these individuals as having won the “genetic lottery,” noting that about 2% to 3% of the population carry variants that partly turn off PCSK9 and appear to enjoy roughly 80% to 90% lower risk of heart disease over a lifetime.[1] Whether one uses the epidemiologic framing or the more vivid clinical metaphor, the point is the same: nature had already run the experiment.
That is what makes these variants so powerful scientifically. For years, cardiometabolic medicine has relied on short- to medium-term interventional trials to infer what decades of lower LDL might mean. PCSK9 loss-of-function carriers offered something even better: a preview of what happens when lower LDL exposure begins at birth and persists across the lifespan.
The field moved quickly from observation to intervention. Monoclonal antibodies such as evolocumab and alirocumab were designed to bind circulating PCSK9 protein and prevent it from driving LDL receptor degradation. These therapies produced striking LDL reductions, often around 60% on top of background statin therapy, and in major outcomes trials they also reduced major adverse cardiovascular events.[9] But monoclonal antibodies did not solve every problem. They are injectable. They are expensive. They still depend on repeated administration. Inclisiran, an siRNA therapy, took the logic one step further by silencing PCSK9 production in the liver and extending dosing to twice a year after the initial loading schedule.[10] That longer interval matters; in a field where adherence is a chronic vulnerability, moving from a daily pill to a twice-yearly injection is a strategic improvement.
However, the endpoint implied by the genetics is not simply twice-yearly treatment. The real lesson of PCSK9 loss-of-function goes beyond the determination that the target is druggable. It is that lifelong reduction in LDL exposure may yield benefits that are difficult to match when treatment starts at age 55 after decades of plaque biology are already underway. But it took another advance in understanding and applying biology to give us the next step in the medicine of cholesterol management.
CRISPR Enters Cardiology
The natural next question is, if some people are born with protective variants that turn down PCSK9 and seem to do well, why not use gene editing to create a similar effect in someone who was not born with that advantage? Would the induced therapeutic effect be as durable as the inherited effect?
Let’s take a moment to review a brief history of CRISPR technology so we understand it’s proposed use in cholesterol control. This has been one of the fastest transformations of basic microbiology into medicine in history, spanning about 33 years. The first observations of unusual repeat DNA sequences in E. coli were made by Yoshizumi Ishino at Osaka University in 1987. These sequences were named CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) by Ruud Jansen in 2002, but the crucial leap occurred in 2005 when Francisco Mojica at the University of Alicante in Spain matched parts of the sequences with pieces of genes from genomes of viruses that consume bacteria. This meant that the bacteria were storing records of past viral invaders and using them to recognize and destroy returning threats. This insight was confirmed by experimental work in 2007. Just four years later, Emmanuelle Charpentier and Jennifer Doudna began work on what would be published as the CRISPER-Cas9 system in June 2012. This tool could be programmed to cut any DNA sequence with precision, and it was rapidly spread through laboratories, along with earning Charpentier and Doudna a 2020 Nobel Prize in Chemistry. CRISPER-edited therapies followed, and the first FDA approved medicine, Casgevy, in 2023. [11]
Getting back to cholesterol management, we find the VERVE-101 is one of the earliest and most closely watched attempts to test the proposition that permanently reducing PCSK9 activity works in humans.[12] This investigational therapy uses in vivo base editing delivered to the liver to disrupt PCSK9 with the goal of permanently reducing its activity with a single dose. Base editing is worth pausing over because it is often misunderstood when collapsed into the catch-all term CRISPR. Rather than cutting both strands of DNA in the classic CRISPR-Cas9 sense, base editing is designed to make a highly targeted change in one DNA letter, a more precise molecular rewrite intended to reduce some of the risks associated with double-strand breaks.[13]
Perhaps the cleanest way to explain how VERVE-101 works is the therapy attempts to rewrite a tiny piece of the liver’s genetic instruction manual so the liver stops supporting high LDL in the same way it did before. It is not a “vaccine” in the immunologic sense, but the metaphor used on the show, a possible “vaccination against high cholesterol”, captures the one-and-done aspiration.[1]
The early human data are both exciting and necessarily incomplete. Interim results from the heart-1 study, which began in 2022, showed that VERVE-101 could produce substantial reductions in PCSK9 protein and LDL cholesterol, with the highest-dose patients showing LDL reductions in the ballpark of roughly 40% to 55% over the follow-up reported publicly.[14] These results are exciting, but the more precise public clinical data to date are still early, small, and evolving, a caveat that matters. Enthusiasm without discipline is a recurring risk in emerging therapeutic platforms, especially in gene editing. Safety is the issue; these are irreversible interventions compared with statins or even monoclonal antibodies, which can be stopped if a problem emerges. Early reports from VERVE-101 have included serious adverse events in a very high-risk patient population, along with the kinds of liver enzyme and safety questions that make regulators appropriately cautious.[14] Even so, the strategic significance is unmistakable. Cholesterol management is no longer confined to pharmacology. It is now a proving ground for whether somatic gene editing can move from rare monogenic disease into the vastly larger domain of common chronic disease. That is a very different commercial, regulatory, and ethical landscape than the one gene therapy first entered, one that raises questions beyond the scope of today’s article, which I may address in the future.
But Wait, There’s More
There are still more discoveries being made in cholesterol biology and its effect on cardiovascular disease, and some of these are likely to continue to transform medicine. High LDL is one of four classic risk factors for heart disease (the others are hypertension, smoking, and type 2 diabetes). Yet a surprising fraction of people hospitalized with heart attacks (up to 25%) have none of the risk factors and often do worse than the “high-risk” patients. Researchers like cardiologist Paul Ridker of Brigham and Women’s Hospital in Boston have worked on this puzzle for years, and their results now suggest that cholesterol forms needlelike crystals that tear artery walls and trigger the vascular inflammation that is atherosclerosis. Another exciting observation came when the work suggested statins damped inflammation as well as reducing cholesterol. A subsequent clinical trial showed people with low LDL but high C-Reactive Protein (CRP), a biomarker for inflammation, would benefit from statin therapy. Another trial provided the first evidence in humans that blocking inflammatory pathways in heart disease patients with high CRP levels is clinically beneficial. The clinical evidence for inflammation is so strong that the American College of Cardiology recommended in 2025 that HCPs routinely screen patients’ CRP levels. Melinda Wenner Moyer’s article in Scientific American is a fantastic overview of the progress in and challenges to inflammation in heart disease.[15] My takeaway? The story of heart disease is far from over.
Three Points to Remember
I wrote this article to remind us of three important points when it comes to developing new medicines:
Understanding basic biology is crucial, and that work takes time and funding without expectation of immediate return;
Biologic systems are so complex that finding a viable point of intervention is also challenging;
Which interventions are the best choice for any person depend on a mix of biological and human factors.
There are unsung heroes and heroines in this story, too. Years of careful work by researchers, clinicians, and physicians in the academe and industry worked together to create the body of evidence that we benefit from every day. Most of these scientists were not cited in this article but are known to their colleagues for their dedication and capacities and may be found in the author lists of publications and employee lists of companies and research institutions everywhere. I’m grateful to have met many and can learn from the work of more. But the overarching story is how medicines that change practice go from “how it works” to “that it works” to “how far can we push it,” and all of it is founded on the patient, careful work of many.
Thanks for reading Thinking Kat! If you found this issue valuable, please pass it to someone else who would benefit.
References
[1] Flatow, I. (Host). (2026, January 21). Looking beyond statins for new ways to lower cholesterol [Audio podcast episode]. In Science Friday. Science Friday Initiative. https://www.sciencefriday.com/segments/new-cholesterol-treatment-crispr/#segment-transcript
[2] Strauss, E. (2023, February 6). Brown & Goldstein: The partnership that sparked a cholesterol revolution. Lasker Foundation. https://laskerfoundation.org/brown-goldstein/
[3] Tobert, J. A. (2024, July 7). Remembering Akira Endo and the beginning of the ‘statin era’. PCSK9 Forum. https://www.pcsk9forum.org/remembering-akira-endo-and-the-beginning-of-the-statin-era/
[4] Cheung, B. M., Lauder, I. J., Lau, C. P., & Kumana, C. R. (2004). Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes. British Journal of Clinical Pharmacology, 57(5), 640–651. https://doi.org/10.1111/j.1365-2125.2003.02060.x
[5] Silverman, M. G., Ference, B. A., Im, K., et al. (2016). Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA, 316(12), 1289–1297. https://doi.org/10.1001/jama.2016.13985
[6] Reston, J. T., Buelt, A., Donahue, M. P., Neubauer, B., Vagichev, E., & McShea, K. (2020). Interventions to improve statin tolerance and adherence in patients at risk for cardiovascular disease: A systematic review for the 2020 U.S. Department of Veterans Affairs and U.S. Department of Defense guidelines for management of dyslipidemia. Annals of Internal Medicine, 173(10), 806–812. https://doi.org/10.7326/M20-4680
[7] Frieden, P., Gagnon, R., Bénard, É., Cossette, B., Bergeron, F., Talbot, D., & Guertin, J. R. (2024). Strategies aiming to improve statin therapy adherence in older adults: A systematic review. BMC Geriatrics, 24, Article 444. https://doi.org/10.1186/s12877-024-05031-z
[8] Folsom, A. R., Peacock, J. M., & Boerwinkle, E. (2009). Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis, 202(1), 211–215. https://doi.org/10.1016/j.atherosclerosis.2008.03.009
[9] Nicholls, S. J. (2023). PCSK9 inhibitors and reduction in cardiovascular events: Implications for clinical practice. Kardiologia Polska (Polish Heart Journal), 81(4), 321–330. https://doi.org/10.33963/KP.a2023.0030
[10] Pirillo, A., & Catapano, A. L. (2022). Inclisiran: How widely and when should we use it? Current Atherosclerosis Reports, 24(10), 803–811. https://doi.org/10.1007/s11883-022-01056-0
[11] Timelines Wiki. (2021, March 29). Timeline of CRISPR. Issa Rice. https://timelines.issarice.com/wiki/Timeline_of_CRISPR
[12] Bellinger, A. (2023, November 8). VERVE-101: CRISPR-based gene editing therapy shows promise in reducing LDL-C and PCSK9 levels in patients with HeFH. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2023/11/08/20/14/sun-445pm-heart1-aha-2023
[13] Lee, R. G., Mazzola, A. M., Braun, M. C., Platt, C., Vafai, S. B., Kathiresan, S., Rohde, E., Bellinger, A. M., & Khera, A. V. (2023). Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation, 147(3), 242–253. https://doi.org/10.1161/CIRCULATIONAHA.122.062132
[14] PACE-CME. (2023, November 13). First-in-human trial results of PCSK9 gene editing therapy in HeFH and ASCVD. PACE-CME. https://pace-cme.org/news/first-in-human-trial-results-of-pcsk9-gene-editing-therapy-in-hefh-and-ascvd/2456566/
[15] Moyer, M.W. (2026, April 14). The hidden cause of heart disease is inflammation. Scientific American. https://www.scientificamerican.com/article/new-evidence-links-heart-disease-to-inflammation-and-drugs-can-stop-it/
When models are trained to please humans, it really shows why you still have to double-check outputs instead of trusting tone or confidence