Positive Effects of CRISPR-Cas9 Gene Editing for Dyslipidemia Endure Through 1 Year

The safety and efficacy of CRISPR-Cas9 gene editing that targets the ANGPTL3 gene for refractory dyslipidemia are durable out to one year, according to extended follow-up data from a clinical trial presented in a late-breaking science session at the European Society of Cardiology Congress 2026. The data were simultaneously published as a research letter in the New England Journal of Medicine.

The report, which describes the longest follow-up for a gene-editing approach to treating lipid disorders by targeting ANGPTL3, clears the way for the next phase of clinical testing of this potential one-time treatment strategy.

“The most compelling feature of gene-editing approaches for treating disease is that they represent the potential for a cure rather than chronic management with medications,” says Cleveland Clinic cardiologist Luke Laffin, MD, the study’s presenter and co-first author. “This first-in-human phase 1a trial is now complete, and the safety and efficacy of the therapy studied, CTX310, were compelling through one year after a one-time treatment for all patients.”

ANGPTL3-targeted gene editing

Development of CTX310 arose from recognition that angiopoietin-like 3 (ANGPTL3), a hepatically produced protein, is an important regulator of lipid metabolism by inhibiting lipoprotein and endothelial lipase. Naturally occurring loss-of-function gene variants for ANGPTL3 are known to result in lifelong reductions in LDL cholesterol, triglycerides and risk of atherosclerotic cardiovascular disease without evidence of adverse effects.

These observations spurred interest in using the in vivo gene-editing technology CRISPR-Cas9 to edit the ANGPTL3 gene to produce a durable genetic modification and resultant permanent reductions in circulating atherogenic lipoproteins. This led to the development of CTX310, a lipid nanoparticle-encapsulated CRISPR-Cas9 formulation with two components — an mRNA and a guide RNA — targeting ANGPTL3 with the aim of inducing a permanent loss-of-function mutation in hepatocytes.

Study design and early results

Initial support for CTX310 came in late 2025 with publication of results from the current study through 60 days on most outcomes. That report, published in the New England Journal of Medicine (2025;393;2119-2130), detailed the phase 1a, open-label, ascending-dose trial in 15 adults with a diagnosis of uncontrolled hypercholesterolemia, moderate to severe hypertriglyceridemia or mixed dyslipidemia. All patients received a one-time infusion of their CTX310 dosage (0.1 to 0.8 mg/kg) based on their estimated lean body weight. The primary end point was safety and tolerability, with effects on lipid biomarkers assessed as secondary endpoints.

Findings through 60 days for all doses showed CTX310 to be well tolerated, with no dose-limiting toxicities or serious adverse events deemed related to CTX310. Several of the highest doses studied reduced ANGPTL3 levels substantially from baseline to 30 days (the latest point assessed at that time) and substantially reduced levels of LDL cholesterol, triglycerides, apolipoprotein B and non-HDL cholesterol through 60 days.

Results at one year

The new report presents results through the study’s full one-year follow-up period. No dose-limiting toxicities related to CTX310 were observed, and no new serious adverse events occurred during the extended follow-up.

Effects on ANGPTL3 level and atherogenic lipoproteins also were sustained through one year. The table below presents mean percentage change from baseline to one year on these measures among patients receiving the highest dose of CTX310 (0.8 mg/kg):

Notable implications for the gene-editing approach

This evidence of enduring effects on lipid biomarkers out to a year is particularly important in the nascent realm of CRISPR gene editing, notes coinvestigator Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute.

“When you edit a gene, it raises the question of whether the effect is temporary or permanent because of cell turnover,” Dr. Nissen says. “Hepatocytes have a turnover rate of nearly 20% per year, and the average age of adult liver cells is less than three years regardless of a person’s age. So what if some of the cells that were not altered are replicating? Does that mean the effect of the gene editing goes away or is diminished? We really need to know if this is a permanent alteration that can enable once-in-a-lifetime treatment. The good news is that the levels of ANGPTL3 and lipids remained low and flat through the full year, which suggests we’re editing the genes so efficiently that when the hepatocytes replicate, the genetic change we’ve induced is replicated along with them.”

“This is encouraging for the entire field of CRISPR,” Dr. Laffin notes, “because it suggests that a one-and-done treatment approach really might be possible for many of the gene-editing targets now being looked at.” Those include gene-editing approaches for lipid disorders that target PCSK9; the study authors note that two manuscripts describing PCSK9 targeting have been published since the report of 60-day results from their study.

Dr. Nissen notes that the FDA has requested that patients in this trial be followed for 15 years, an unprecedented duration of required surveillance. Although efficacy will be closely monitored during that period, the FDA request is for reasons of safety rather than efficacy. “We need to ensure there are no downstream safety issues from editing a gene, such as malignancy,” he explains. “This type of very long-term follow-up will have to be done for most of the CRISPR-based therapies.”

Phase 1b trial will launch soon

He and Dr. Laffin are now looking ahead to further clinical testing.

“Although we’re excited by the durability of these results, we’re even more excited about the data we will glean from the next phase of the trial, phase 1b,” Dr. Laffin says. “In that phase all patients will receive a similar dose of CTX310 and we will look at the treatment's efficacy in specific lipid disorder cohorts, not the heterogeneous mix of participants that were studied in phase 1a.”

He adds that his research group’s enthusiasm about their findings has been matched by interest from potential patients. “Following our initial publication, many patients have contacted us to inquire about being a part of upcoming trials,” Dr. Laffin concludes.