Researchers from the University of Barcelona and the University of Oregon have developed a promising new strategy to control cholesterol levels and potentially reduce the risk of atherosclerosis, a condition caused by the buildup of fatty plaques in artery walls.
The researchers focused on hypercholesterolemia, a condition in which high cholesterol levels damage arteries and increase the risk of cardiovascular disease. Their findings suggest that a new DNA-based therapy could offer a more targeted and potentially safer alternative to existing cholesterol-lowering treatments.
The study findings were published in the journal Biochemical Pharmacology.
Study Targets PCSK9 Protein Linked to High Cholesterol
The research team targeted PCSK9, a protein that plays a central role in regulating levels of low-density lipoprotein cholesterol (LDL-C), commonly referred to as “bad” cholesterol.
Normally, PCSK9 binds to LDL receptors on cells and reduces their ability to remove cholesterol from the bloodstream. Consequently, high PCSK9 levels decrease the number of available LDL receptors, leading to the accumulation of LDL cholesterol in the blood and increasing cardiovascular risk.
To address this problem, the researchers developed a strategy to block the production of PCSK9 using specialised DNA-based molecules known as polypurine hairpins (PPRHs).
Polypurine Hairpins Block Cholesterol Gene Activity
Polypurine hairpins are short DNA strands capable of binding very precisely to specific DNA or RNA sequences and blocking gene activity.
In this study, the researchers used PPRHs to prevent the transcription of the PCSK9 gene. As a result, LDL receptor levels increased, enabling cells to absorb more cholesterol from the bloodstream and reducing cholesterol accumulation in the arteries.
Importantly, this approach may help avoid side effects commonly associated with statin therapy, particularly muscle-related complications.
Researchers Identify Two Effective PPRHs
The study describes, for the first time, how two specific PPRHs—HpE9 and HpE12—successfully reduced both PCSK9 RNA and protein levels while simultaneously increasing LDL receptor levels.
Explaining the mechanism, Professor Carles J. Ciudad from the Department of Biochemistry and Physiology at the University of Barcelona said:
“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.”
He further noted that this interaction blocks gene transcription and interferes with the activity of RNA polymerase or transcription factors.
Researchers Report Strong Results in Laboratory and Animal Studies
The research team tested the therapy in laboratory-grown liver cells and transgenic mice carrying the human PCSK9 gene.
The results demonstrated significant reductions in cholesterol-related markers.
“The results show that both HpE9 and HpE12 are highly effective in HepG2 cells. HpE12 decreases PCSK9 RNA levels by 74% and protein levels by 87%,” said Professor Verònica Noé from the University of Barcelona.
She further added, “In the case of transgenic mice, a single injection of HpE12 reduces plasma PCSK9 levels by 50% and cholesterol levels by 47% on the third day.”
Research Team and Funding Support
As reported by Science Daily, the study was led by Professor Carles J. Ciudad and Professor Verònica Noé from the University of Barcelona’s Faculty of Pharmacy and Food Sciences and the Institute of Nanoscience and Nanotechnology (IN2UB).
The researchers collaborated with Nathalie Pamir at the University of Oregon in Portland, United States.
The Spanish Ministry of Science, Innovation and Universities (MICINN) and the National Institutes of Health (NIH) in the United States funded the research.
New Approach Could Offer Alternative to Statins
In recent years, PCSK9 has emerged as a major target for cholesterol-lowering therapies. Current approaches include gene-silencing technologies such as siRNAs, antisense oligonucleotides, and CRISPR-based therapies.
Existing treatments targeting PCSK9 already include Inclisiran, an siRNA-based therapy, as well as monoclonal antibodies such as evolocumab and alirocumab.
However, researchers believe PPRHs may provide several distinct advantages.
“PPRHs, especially HpE12, are therapeutic oligonucleotides with many advantages, including low cost of synthesis, stability and lack of immunogenicity,” the researchers noted.
They further added that a PPRH-based approach targeting PCSK9 may avoid side effects such as the myopathies commonly associated with statin therapy.
Findings Could Lead to Safer Cholesterol Treatments
If future studies confirm these findings, the new DNA-based strategy could offer a safer, more targeted, and cost-effective method to lower cholesterol levels and reduce the risk of heart disease and atherosclerosis.