In a breakthrough that could change the future of cardiovascular treatment, scientists from the University of Barcelona and the University of Oregon have unveiled a new gene-targeting therapy designed to lower cholesterol levels safely and effectively — without the side effects commonly linked to statins. The innovative technique, published in Biochemical Pharmacology, could mark a major step forward in the global fight against heart disease and atherosclerosis.
A New Hope for Cholesterol Management
Excessive cholesterol in the bloodstream — known medically as hypercholesterolemia — remains one of the leading causes of heart attacks and strokes worldwide. While statins have long been the frontline treatment, millions of patients either cannot tolerate them or fail to achieve adequate cholesterol control.
Now, a transatlantic research team led by Professors Carles J. Ciudad and Verònica Noé from the University of Barcelona, in collaboration with Professor Nathalie Pamir of the University of Oregon, has developed a new therapeutic approach that directly targets a key regulator of cholesterol metabolism: the PCSK9 protein.
Funded by Spain’s Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH), the study introduces a molecular strategy using polypurine hairpins (PPRHs) — tiny DNA-based structures that can silence specific genes and help regulate cholesterol at the source.
Targeting the PCSK9 Protein
Over the past decade, PCSK9 (protein convertase subtilisin/kexin type 9) has become a central target in cholesterol therapy. The enzyme naturally limits the number of LDL receptors (LDLR) on cell surfaces — receptors responsible for clearing “bad” LDL cholesterol from the blood. When PCSK9 activity rises, LDL receptors decrease, allowing cholesterol levels to climb.
The new study takes a direct approach: PPRHs are designed to stop the PCSK9 gene from producing this enzyme, thereby restoring normal LDL receptor levels and improving the body’s ability to clear cholesterol from the bloodstream.
“This strategy allows us to precisely inhibit PCSK9 production at the genetic level, without interfering with other cellular processes,” said Professor Ciudad. “The result is a significant reduction in circulating LDL cholesterol, and potentially, a safer and more effective way to prevent atherosclerosis.”
How Polypurine Hairpins Work
Polypurine hairpins are single-stranded DNA molecules capable of binding specifically to complementary sequences in DNA or RNA. This interaction effectively “locks out” transcription — the process by which genes create proteins.
In this study, researchers designed two PPRHs, named HpE9 and HpE12, which target specific regions (exons 9 and 12) of the PCSK9 gene. Laboratory tests showed both molecules significantly reduced PCSK9 expression while increasing LDL receptor levels.
“The arm of each hairpin binds directly to the gene sequence through Watson-Crick base pairing, which prevents RNA polymerase from reading the gene,” explained Ciudad. “It’s a highly selective mechanism with minimal risk of off-target effects.”
Strong Results in Mice and Human Cells
The therapy was first validated in HepG2 human liver cells, where HpE12 decreased PCSK9 RNA by 74% and protein levels by an impressive 87%. When tested in transgenic mice carrying the human PCSK9 gene, a single injection of HpE12 reduced plasma PCSK9 levels by 50% and total cholesterol levels by 47% within just three days.
“These results are very encouraging,” said Professor Verònica Noé. “Not only did we see a significant drop in cholesterol, but the treatment showed excellent stability and no signs of immune response or toxicity.”
Toward Statin-Free Cholesterol Control
Since the discovery of PCSK9’s role in cholesterol metabolism, several drugs have been developed to inhibit it, including monoclonal antibodies (like evolocumab and alirocumab) and siRNA-based therapies such as Inclisiran. While these treatments have proven effective, they can be expensive and require repeated injections or complex manufacturing processes.
The new PPRH-based approach could offer a simpler, more affordable alternative. Unlike antibody therapies, PPRHs are small, chemically stable, and easy to synthesize, potentially making large-scale production more accessible.
“PPRHs, especially HpE12, stand out because they combine low cost, high stability, and no immunogenicity,” said Noé. “This means patients could receive long-lasting cholesterol control without the muscle pain or liver issues sometimes associated with statins.”
A Future Path for Cardiovascular Medicine
Experts say the development of PPRH-based gene silencers could transform preventive cardiology. By addressing cholesterol imbalance at the genetic level, such treatments might eventually replace or complement existing therapies for patients at high risk of cardiovascular disease.
However, the researchers caution that more work lies ahead. Clinical testing in humans will be necessary to confirm safety, dosage, and long-term effects. Still, the early evidence is strong enough to generate optimism among cardiovascular specialists.
“This research represents a new frontier,” noted Professor Pamir from the University of Oregon. “If further studies confirm these findings, PPRHs could become a foundational therapy — one that provides effective cholesterol control without the drawbacks of current drugs.”
As the global burden of heart disease continues to rise, innovations like this may help redefine how doctors manage cholesterol and protect arterial health. For millions of patients struggling with statin intolerance or limited treatment options, the era of gene-guided cholesterol therapy may soon be on the horizon.