Novel DNA treatment cuts cholesterol 47% in mice, offering statin alternative

A team of researchers at the University of Barcelona has designed a new approach to lowering cholesterol that sidesteps the traditional statin pathway entirely. Instead of relying on the drugs that have dominated cardiovascular medicine for decades, they engineered short DNA molecules called polypurine hairpins to silence the gene responsible for producing PCSK9, a protein that interferes with the body's ability to remove cholesterol from the bloodstream. In tests, their most effective molecule—called HpE12—reduced PCSK9 protein by 87 percent in human liver cells and cut overall cholesterol levels by 47 percent in genetically modified mice after a single injection.

The mechanism is straightforward in principle. Cells use specialized receptors to capture LDL cholesterol circulating in the blood. PCSK9 acts as a saboteur in this process, reducing the number of receptors available on cell surfaces. With fewer receptors to do the work, more cholesterol stays in circulation, accumulating in the bloodstream and eventually contributing to the fatty plaques that narrow arteries. The Barcelona team, led by professors Carles J. Ciudad and Verònica Noé, along with collaborator Nathalie Pamir from the University of Oregon, took aim at the root cause: they designed molecules that could bind to specific sequences within the PCSK9 gene itself and disrupt its transcription—the process by which cells convert genetic instructions into the proteins they need to function.

Polypurine hairpins are oligonucleotides, short single-stranded DNA sequences engineered to recognize and attach to precise genetic targets. Once bound, they interfere with the molecular machinery that reads genes and produces RNA. The researchers tested two variants, HpE9 and HpE12, both of which successfully reduced PCSK9 RNA and protein while simultaneously increasing levels of LDLR, the receptor that helps cells absorb cholesterol. The binding occurs through Watson-Crick bonds—the same hydrogen bonds that hold the two strands of a DNA double helix together—and disrupts either the activity of RNA polymerase, the enzyme that manufactures RNA, or the attachment of transcription factors that initiate gene reading.

When the team moved from cell cultures to living organisms, HpE12 delivered the strongest results. A single injection into transgenic mice engineered to carry the human PCSK9 gene reduced circulating PCSK9 levels by 50 percent and total cholesterol by 47 percent by the third day. These findings, published in Biochemical Pharmacology, suggest that suppressing PCSK9 through this method increases the availability of LDL receptors and allows cells to extract more cholesterol from circulation—potentially reducing the cholesterol available to form arterial plaques.

The approach arrives in a landscape already crowded with PCSK9-targeting therapies. Inclisiran, an siRNA-based drug, works through a different gene-silencing mechanism. Monoclonal antibodies like evolocumab and alirocumab bind directly to PCSK9 protein itself. Yet the Barcelona researchers argue that polypurine hairpins offer practical advantages that could make them competitive. The molecules are relatively inexpensive to synthesize, remain stable in the body, and appear unlikely to trigger immune responses—a significant consideration given that some existing cholesterol drugs, particularly statins, can cause muscle pain and other side effects in a subset of patients. The researchers note that a PPRH-based approach would avoid the myopathies associated with statin therapy.

The work was supported by funding from Spain's Ministry of Science, Innovation and Universities and the U.S. National Institutes of Health, reflecting the international interest in expanding the toolkit for cholesterol management. Yet a crucial gap remains. The cholesterol reduction was demonstrated in mice, not humans. Before HpE12 or similar molecules could move toward clinical use, researchers would need to conduct human trials to establish whether the treatment is safe and effective in people, whether the effects persist over time, and what dosing regimens might be optimal. If those studies succeed, this DNA-based approach could eventually become another option for patients seeking to lower their LDL cholesterol and reduce their cardiovascular risk.