New treatment cuts cholesterol by nearly 50%, without statins or side effects

The research team created a strategy to block the activity of PCSK9, a protein that plays a crucial role in controlling the amount of low-density lipoprotein cholesterol (LDL-C), often called "bad" cholesterol, in the bloodstream. This innovative approach relies on molecules called polypurine hairpins (PPRHs), which help cells absorb more cholesterol and prevent its accumulation in arteries, without producing the side effects often linked to statin drugs.

The study, published in Biochemical Pharmacology, was led by professors 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 from the University of Oregon in Portland (United States). Funding came from Spain's Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH).

Targeting the PCSK9 Protein

PCSK9 (protein convertase subtilisin/kexin type 9) has become a major target for cholesterol treatment and cardiovascular protection over the past decade. This enzyme binds to receptors on cell surfaces that normally capture LDL cholesterol. When PCSK9 binds to these receptors, it reduces their number, leading to higher LDL cholesterol levels circulating in the blood and increasing the risk of hypercholesterolemia.

The new technique developed by the team uses PPRHs to halt the transcription of specific genes, effectively silencing their expression. In this study, PPRHs were used to inhibit the PCSK9 gene, resulting in an increase in LDL receptors (LDLR) and improved cholesterol uptake by cells. This mechanism helps reduce both circulating cholesterol and the risk of plaque buildup in arteries.

How Polypurine Hairpins Work

PPRHs are single-stranded DNA molecules, known as oligonucleotides, that can bind precisely to complementary DNA or RNA sequences. The research demonstrated for the first time that two specific PPRHs, HpE9 and HpE12, lower PCSK9 RNA and protein levels while raising LDLR 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 binding inhibits gene transcription and the action of RNA polymerase or the binding of transcription factors.

The new therapeutic technique has been validated in vivo in transgenic mice expressing the human PCSK9 gene. "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.

Toward Statin-Free Cholesterol Control

Since PCSK9 was defined as a significant target in plasma cholesterol-lowering therapy, several therapeutic approaches have been designed to lower or block its action. For example, gene silencing with siRNAs, antisense oligonucleotides or the CRISPR technique. In particular, Inclisiran, an siRNA agent against PCSK9, and the monoclonal antibodies such as evolocumab and alirocumab stand out.

"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.