One-and-Done CRISPR Gene Edit Slashes LDL and Triglycerides in Early Human Trial

Single infusion of CRISPR therapy lowers lipids in a small Phase 1 trial

Lowering cholesterol and triglycerides is a proven way to reduce heart-disease risk. A small Phase 1 trial at the Cleveland Clinic suggests a single infusion of a CRISPR-based gene-editing therapy can produce large, sustained reductions in both LDL cholesterol and triglycerides over at least six months.

Study design and results

The trial, led by Dr. Luke Laffin with senior investigator Dr. Steven Nissen, enrolled 15 adults whose cholesterol and/or triglycerides remained high despite standard therapies, including statins. Participants received a one-time infusion of a CRISPR therapy developed by CRISPR Therapeutics; doses varied because the primary goal of this early study was to evaluate safety and detect initial signs of efficacy.

Those who received the highest dose experienced roughly a 50% reduction in LDL ("bad") cholesterol and about a 55% reduction in triglycerides at six months compared with baseline. The effect on the protein encoded by the targeted gene—ANGPTL3—was dose dependent: higher doses produced greater reductions in circulating ANGPTL3 protein.

How the therapy works

The therapy targets ANGPTL3, a gene known from human genetics to influence both cholesterol and triglyceride levels. People with natural loss-of-function variants in ANGPTL3 typically have lower levels of LDL and triglycerides and lower rates of heart disease without clear adverse effects. The experimental CRISPR treatment delivers gene-editing "scissors" packaged in a lipid nanoparticle designed to home to liver cells, where many blood lipids are produced, and disrupts ANGPTL3 so it becomes nonfunctional.

Durability and preclinical data

In nonhuman primate studies, CRISPR Therapeutics reported sustained lipid reductions for up to two years after a single treatment. In the current human trial, researchers observed sustained decreases for up to six months and plan longer follow-up. The U.S. Food and Drug Administration recommends long-term monitoring—often many years—for gene-editing therapies to track durability and late adverse events.

Safety and remaining questions

CRISPR-based therapies carry risks. A different CRISPR program by another company (Intellia) was paused after participants developed severe liver toxicity, underscoring that delivery method and editing chemistry matter. In the Cleveland Clinic trial, one participant died six months after infusion; investigators say the patient had advanced atherosclerotic disease and do not believe the death was related to the therapy, but they emphasize the need for larger trials and continued vigilance.

“This is the first time anybody has ever edited a gene related to cholesterol metabolism and published results in a peer-reviewed journal,” said Dr. Steven Nissen. “The results are very encouraging, but we need bigger studies to confirm safety and efficacy.”

Potential advantages and future directions

Investigators and the sponsor highlight potential benefits versus current lipid therapies: statins require daily dosing and adherence is imperfect, while PCSK9 inhibitors require repeated injections and mainly affect cholesterol rather than triglycerides. ANGPTL3 disruption could lower both LDL and triglycerides with a single, one-time treatment. CRISPR Therapeutics—whose work includes CRISPR-based treatments for sickle-cell disease and beta thalassemia—plans larger Phase 2 studies, initially in patients who do not respond adequately to current lipid-lowering therapies and eventually in higher-risk but asymptomatic populations for prevention.

While the early efficacy signals are promising, the treatment must be tested in larger, longer, and more diverse trials to confirm durability, safety (including off-target edits and liver effects), and clinical benefit in preventing heart attacks and other cardiovascular events.

Bottom line: A one-time CRISPR infusion targeting ANGPTL3 produced large, dose-dependent reductions in LDL and triglycerides at six months in 15 patients, but further study is required to establish long-term safety and effectiveness before clinical use.