A new Phase 1 trial produced encouraging safety and efficacy results for a CRISPR-based gene therapy that silences a gene important for lipid regulation. This therapy might increase adherence and reduce side effects [1].
Addressing the adherence problem
High levels of LDL cholesterol (LDL-C) and triglycerides are a major risk factor for cardiovascular disease and mortality. They can be caused by genetic variations, other diseases like hypothyroidism and diabetes, and environmental factors such as modern eating habits [2]. This dyslipidemia is also age-related, with LDL-C levels tending to rise in older people [3].
Effective therapies, especially against high LDL-C, exist. Statins, a class of cholesterol-lowering drugs that lead to robust reductions in cardiovascular events and related mortality, are a go-to first-line option. However, low adherence and side effects remain a problem, with many patients discontinuing treatment within a year.
In this trial, the company CRISPR Therapeutics tested an experimental gene therapy agent, CTX310, against abnormally high LDL-C and triglyceride levels. The therapy, based on the CRISPR platform, silences the production of ANGPTL3, a protein that is secreted primarily by the liver and plays a key role in regulating blood lipid levels. This protein inhibits the enzymes lipoprotein lipase (LPL) and endothelial lipase, which are crucial for breaking down triglycerides and remodeling high-density lipoprotein (HDL). As a result, higher ANGPTL3 levels lead to higher levels of circulating triglycerides and cholesterol in the blood.
LDL and triglycerides halved
This multicenter, open-label, single-ascending-dose study was conducted in Australia, New Zealand, and the UK and involved 15 adults with uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia. The participants’ median age was 53 years with a range of 31 and 68. 87% were male, 40% had a history of atherosclerotic cardiovascular disease, and 40% had familial hypercholesterolemia, with 33% carrying confirmed genetic mutations. Background lipid-lowering therapies included statins (60%), ezetimibe (53%), and PCSK9 monoclonal antibodies (40%).
The elements of the CRISPR system (SpCas9 mRNA + a single guide RNA targeting ANGPTL3) were encapsulated in lipid nanoparticles (LNPs). The treatment was administered once via IV infusion, and the follow-up period prior to publication of the results was 60 days with a one-year continuation.
The treatment caused a drastic decline in the average ANGPTL3 level at higher doses: up to -79.7% for the 0.7 mg/kg dose. The average level was actually slightly, but not significantly, higher for 0.8 mg/kg: -73.2%. Most importantly, the treatment significantly lowered mean LDL-C and triglyceride levels at 0.8 mg/kg; LDL-C was down by 48.9% and triglycerides by 55.2% at this dose.
Why do we need ANGPTL3, if silencing it seems to benefit us? Like some other genes, it might have lost its evolutionary sense as food became more abundant. By shunting post-meal triglycerides to fat tissue for storage, ANGPTL3 might have helped our ancestors to eat large meals when food was available without burdening the heart and muscle with excess lipid.
Waiting for more robust studies
The trial reported minimal adverse events, indicating a favorable safety profile for CTX310. No dose-limiting toxic effects were observed. However, variability in lipid-lowering effects was noted among participants receiving the same CTX310 dose.
According to the researchers, this variability was not simply dose-related: editing efficacy and lipid responses may be influenced by hepatic steatosis, inflammation, and pre-existing genetic/metabolic profiles, and the cohort itself had mixed phenotypes, as some were primarily high LDL-C, and others had high triglycerides. This likely contributed to differences in lipid-lowering effects even at the same dose. The team calls for more rigorous studies to identify patient-specific predictors and to optimize dosing.
The sample size was also extremely small: only 2-4 patients received each dose, resulting in low statistical power for each cohort. The primary outcome of this Phase 1 trial was safety, and subsequent phases will provide more robust efficacy results.
The cohort was heavily male, and the authors themselves note that few women were enrolled, limiting subgroup assessment. Known sex differences exist in lipid biology, such as menopause-related shifts [4], and they affect responses to biological interventions and in the way people age, so generalizability from this sample is uncertain.
Finally, the effect size was not necessarily larger than that of some existing therapies. However, those require constant administration and can cause considerable side effects.
“Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease,” said Steven E. Nissen, M.D., FAHA, a co-author of the study and chief academic officer at the Cleveland Clinic Heart, Vascular and Thoracic Institute. “Many patients stop taking their cholesterol medications within the first year. The possibility of a one-time treatment with lasting effects could be a major clinical advance.”
Literature
[1] Laffin, L. J., Nicholls, S. J., Scott, R. S., Clifton, P. M., Baker, J., Sarraju, A., … & Nissen, S. E. (2025). Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. New England Journal of Medicine.
[2] Yanai, H., & Yoshida, H. (2021). Secondary dyslipidemia: its treatments and association with atherosclerosis. Global health & medicine, 3(1), 15-23.
[3] Liu, H. H., & Li, J. J. (2015). Aging and dyslipidemia: a review of potential mechanisms. Ageing research reviews, 19, 43-52.
[4] Palmisano, B. T., Zhu, L., Eckel, R. H., & Stafford, J. M. (2018). Sex differences in lipid and lipoprotein metabolism. Molecular metabolism, 15, 45-55.
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