The research team focused on PCSK9, a protein that plays a central role in regulating levels of low-density lipoprotein cholesterol (LDL-C), often called "bad" cholesterol. They designed a method to block the production of this protein using specialized DNA-based molecules known as polypurine hairpins (PPRH). By suppressing PCSK9, the treatment helps cells absorb more cholesterol, reducing the amount circulating in the blood and limiting buildup in the arteries. Importantly, this approach may avoid the side effects commonly linked to statin medications.

The findings were published in the journal Biochemical Pharmacology. The study was led by Carles J. Ciudad and Verònica Noé from the University of Barcelona's Faculty of Pharmacy and Food Sciences and the Institute of Nanoscience and Nanotechnology (IN2UB), working with Nathalie Pamir at the University of Oregon in Portland (United States). Funding came from the Spanish Ministry of Science, Innovation and Universities (MICINN) and the National Institutes of Health (NIH) in the United States.

How Polypurine Hairpins Block a Key Cholesterol Protein

PCSK9 (protein convertase subtilisin/kexin type 9) has become an important target in recent years for therapies aimed at lowering cholesterol and reducing cardiovascular risk. The protein works by attaching to LDL receptors on cells, limiting their ability to remove cholesterol from the bloodstream. When PCSK9 levels are high, fewer receptors are available, causing LDL cholesterol to accumulate in the blood.

Polypurine hairpins (PPRHs) offer a way to interrupt this process at the genetic level. These molecules are short strands of DNA that can bind very precisely to specific DNA or RNA sequences and block gene activity. In this case, PPRHs prevent the PCSK9 gene from being transcribed, which leads to an increase in LDLR receptor levels and improves the body's ability to pull cholesterol out of circulation. As a result, overall cholesterol levels drop and the risk of plaque formation is reduced.

The study describes for the first time how two specific PPRHs, called HpE9 and HpE12, reduce both PCSK9 RNA and protein while boosting LDL receptor levels.

"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," notes Professor Carles J. Ciudad, from the Department of Biochemistry and Physiology. This interaction blocks gene transcription and interferes with the activity of RNA polymerase or transcription factors.

Strong Results in Cells and Animal Models

The researchers tested the therapy in laboratory-grown liver cells and in transgenic mice that carry the human PCSK9 gene. The results were significant.

"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%. 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," says Professor Verònica Noé.

A Potential Alternative to Statins

Since PCSK9 has become a major target for cholesterol-lowering therapies, several approaches have been developed to block its effects. These include gene-silencing technologies such as siRNAs, antisense oligonucleotides, and CRISPR-based methods. Existing treatments like Inclisiran, an siRNA therapy, and monoclonal antibodies such as evolocumab and alirocumab are already in use.

However, PPRHs may offer unique advantages. "PPRHs, especially HpE12, are therapeutic oligonucleotides with many advantages, including low cost of synthesis, stability and lack of immunogenicity. In addition, such a PPRH-based approach against PCSK9 would not lead to side effects such as the myopathies associated with statin therapy," the experts conclude.

If confirmed in further studies, this new strategy could provide a safer and more targeted way to lower cholesterol and reduce the risk of heart disease.