This therapy slashes bad cholesterol by nearly 50% without statins or side effects

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A new kind of cholesterol treatment is emerging from the lab—and it does not rely on statins. Researchers from the University of Barcelona and the University of Oregon have developed a DNA‑based therapy that switches off a key cholesterol‑controlling gene, cutting “bad” LDL cholesterol by nearly 50% in animal models without the muscle pain and other side effects that drive many patients to abandon traditional drugs.

Turning down cholesterol at the gene level

At the heart of this breakthrough is PCSK9, a protein that tells the body to remove LDL receptors from the surface of liver cells. When PCSK9 is overactive, fewer receptors are available to clear LDL from the blood, and cholesterol levels climb, increasing the risk of atherosclerosis and heart attack. The new strategy uses tiny DNA molecules called polypurine reverse Hoogsteen hairpins—PPRHs for short—to silence the PCSK9 gene before it can make this protein.

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Crystal Structure of PCSK9
Source: PDB

Two specially designed PPRHs, named HpE9 and HpE12, bind precisely to sections of the PCSK9 gene and block its transcription, dramatically lowering the amount of PCSK9 RNA and protein produced. As PCSK9 drops, LDL receptors rebound, pulling more cholesterol out of circulation and reducing the fatty buildup that clogs arteries over time.

A study led by the University of Barcelona and the University of Oregon presents a new methodology — based on molecules known as polypurine hairpins — capable of acting on the PCSK9 protein, a known therapeutic target for reducing blood cholesterol. Credit: Biochemical Pharmacology

Nearly 50% lower cholesterol in mice

To test the approach, scientists first showed that HpE9 and HpE12 sharply reduced PCSK9 levels in human liver‑cell models while boosting LDL receptors. They then moved to transgenic mice engineered to express human PCSK9. A single injection of HpE12 slashed plasma PCSK9 by about 50% and total cholesterol by roughly 47% within three days, with no detected changes in body weight, liver enzymes, or inflammatory markers compared with control animals.​

These results suggest that PPRH therapy can produce a powerful, rapid cholesterol‑lowering effect while appearing well tolerated—at least in the short term and in preclinical models. The team notes that PPRHs are relatively cheap to synthesize, chemically stable, and non‑immunogenic, potentially making them more accessible than some current biologic PCSK9 inhibitors. ​

A possible alternative for statin‑intolerant patients

PCSK9 has already become a major target in cardiology: monoclonal antibodies, small interfering RNAs like inclisiran, and other agents are used or tested to complement or replace statins when needed. What sets the PPRH approach apart is its combination of precision gene silencing with comparatively simple DNA chemistry, which could translate into lower costs and flexible dosing if human trials confirm the benefits.​

For people who cannot tolerate statins because of muscle pain or other side effects, a therapy that lowers LDL so dramatically without triggering myopathy would be especially attractive. However, experts emphasize that this work is still in the experimental stage: results so far come from cell cultures and mice, not from large clinical trials in patients with high cholesterol. ​

What comes next

Before PPRH‑based treatments can reach clinics, researchers must show that they are safe, durable, and effective in humans, and work out practical issues such as delivery methods and dosing schedules. Still, the concept is a glimpse of where cardiovascular medicine is heading—away from one‑size‑fits‑all pills and toward highly targeted, gene‑level interventions.​

If future studies succeed, a simple injection of DNA hairpins that tells the body to clear its own cholesterol more efficiently could become a powerful new option alongside, or even instead of, statins. For millions living with stubbornly high LDL, that prospect is more than just a scientific curiosity—it is a potential lifeline.

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