Researchers from the University of Barcelona and the University of Oregon report that short DNA molecules known as polypurine reverse Hoogsteen hairpins (PPRHs) suppressed the PCSK9 gene and reduced blood cholesterol in a mouse model. In transgenic mice carrying the human PCSK9 gene, a single injection of one candidate (HpE12) cut plasma PCSK9 by 50% and total cholesterol by 47% three days later, according to findings published in Biochemical Pharmacology.
High levels of low-density lipoprotein cholesterol (LDL-C)—often referred to as “bad” cholesterol—are a major risk factor for atherosclerosis, a condition in which fatty plaques accumulate in artery walls.
Researchers at the University of Barcelona, working with collaborators in Oregon, targeted PCSK9 (proprotein convertase subtilisin/kexin type 9), a protein that reduces the availability of LDL receptors on cells. With fewer LDL receptors, less LDL cholesterol is removed from the bloodstream.
The team’s approach uses DNA-based molecules called polypurine reverse Hoogsteen hairpins (PPRHs). These short DNA strands are designed to bind to specific sequences associated with the PCSK9 gene and interfere with transcription, ultimately reducing production of PCSK9 and increasing LDL receptor levels.
The study—published in Biochemical Pharmacology (2025; 238: 116976)—was led by Carles J. Ciudad and Verònica Noé of the University of Barcelona’s Faculty of Pharmacy and Food Sciences and the Institute of Nanoscience and Nanotechnology (IN2UB), in collaboration with Nathalie Pamir of the University of Oregon in Portland.
“Specifically, one of the arms of each chain of the HpE9 and HpE12 polypurines binds specifically to polypyrimidine sequences of exons 9 and 12 of PCSK9, respectively, via Watson-Crick bonds,” Ciudad said in a university statement.
In experiments in HepG2 liver cells, one of the candidates—HpE12—reduced PCSK9 RNA levels by 74% and PCSK9 protein levels by 87%, the researchers reported.
In transgenic mice that express the human PCSK9 gene, a single injection of HpE12 reduced plasma PCSK9 levels by 50% and reduced total cholesterol levels by 47% on the third day after dosing, the researchers said.
The researchers argued that PPRHs could have practical advantages as therapeutic oligonucleotides, including relatively low synthesis costs, stability, and a lack of immunogenicity. They also suggested that a PCSK9-targeting strategy like this could avoid muscle-related side effects (myopathies) that have been reported with statin therapy—though the work described so far is limited to laboratory and animal experiments.
Several PCSK9-targeting medicines are already used clinically, including inclisiran (an siRNA therapy) and monoclonal antibodies such as evolocumab and alirocumab. The authors described PPRHs as another gene-silencing approach that, if supported by further studies, could expand options for lowering cholesterol.
The work was funded by Spain’s Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH).
