Elevated cholesterol levels in the blood can lead to hypercholesterolemia, a condition that harms arteries and heightens the risk of heart disease. Recently, researchers from the University of Barcelona and the University of Oregon have come up with an innovative method to manage cholesterol levels, potentially offering a new strategy against atherosclerosis, which happens when fat deposits accumulate in artery walls.
The research team turned their attention to PCSK9, a protein vital for controlling low-density lipoprotein cholesterol (LDL-C), often referred to as “bad” cholesterol. They developed a technique to inhibit the production of this protein using specially designed DNA-based molecules known as polypurine hairpins (PPRH). By reducing PCSK9 levels, the treatment enables cells to absorb more cholesterol, thereby decreasing its presence in the bloodstream and minimizing arterial buildup. Notably, this method may also sidestep the side effects commonly associated with statin medications.
The results were published in Biochemical Pharmacology. The study was spearheaded by Carles J. Ciudad and Verònica Noé from the University of Barcelona’s Faculty of Pharmacy and Food Sciences, alongside Nathalie Pamir from the University of Oregon in Portland. The research received funding from the Spanish Ministry of Science, Innovation and Universities and the National Institutes of Health in the U.S.
How Polypurine Hairpins Block a Key Cholesterol Protein
In recent years, PCSK9 (protein convertase subtilisin/kexin type 9) has emerged as a crucial target for therapies aimed at lowering cholesterol and mitigating cardiovascular risk. This protein functions by binding to LDL receptors on cell surfaces, restricting their ability to clear cholesterol from the bloodstream. When PCSK9 levels are high, fewer receptors are available, which leads to elevated levels of LDL cholesterol.
Polypurine hairpins (PPRHs) present a way to disrupt this process at the genetic level. These molecules are short strands of DNA that can attach precisely to specific DNA or RNA sequences, blocking gene activity. Specifically, PPRHs inhibit the transcription of the PCSK9 gene, which ultimately increases LDL receptor levels and enhances the body’s cholesterol uptake. This results in lower overall cholesterol levels and a reduced risk of plaque formation.
The study marks the first time two specific PPRHs, identified as HpE9 and HpE12, are shown to lower both PCSK9 RNA and protein levels while increasing LDL receptor levels.
“Specifically, one of the arms of each chain of HpE9 and HpE12 binds to polypyrimidine sequences of exons 9 and 12 of PCSK9, respectively, through Watson-Crick bonds,” explains Professor Carles J. Ciudad from the Department of Biochemistry and Physiology. This interaction halts gene transcription and disrupts RNA polymerase activity or transcription factors.
Strong Results in Cells and Animal Models
The researchers evaluated the therapy in liver cells grown in the lab and in transgenic mice carrying the human PCSK9 gene. The outcomes were noteworthy.
“The findings indicate that both HpE9 and HpE12 demonstrate high effectiveness in HepG2 cells. HpE12 reduces PCSK9 RNA levels by 74% and protein levels by 87%. Furthermore, in transgenic mice, a single dosage of HpE12 decreased plasma PCSK9 levels by 50% and cholesterol levels by 47% by day three,” notes Professor Verònica Noé.
A Potential Alternative to Statins
As PCSK9 has become a focal point for cholesterol-lowering therapies, various strategies have been designed to counter its effects. These include gene-silencing technologies like siRNAs, antisense oligonucleotides, and CRISPR methods. Current treatments such as Inclisiran, a siRNA therapy, along with monoclonal antibodies like evolocumab and alirocumab, are already in practice.
However, PPRHs might present distinct benefits. “PPRHs, especially HpE12, are therapeutic oligonucleotides that offer several advantages, including lower synthesis costs, stability, and minimal immunogenicity. Moreover, a PPRH-based method targeting PCSK9 would likely not cause side effects like the myopathies seen with statin therapies,” the researchers conclude.
If confirmed through further studies, this novel approach could provide a safer and more precise method for reducing cholesterol levels and lowering heart disease risk.
