Researchers from the University of Barcelona and the University of Oregon have developed a DNA-based treatment that targets the PCSK9 gene to lower cholesterol levels without the side effects of statins. Using polypurine hairpins, the therapy increases cholesterol uptake by cells and reduces artery-clogging lipids in animal models. The findings, published in Biochemical Pharmacology, suggest a safer alternative for preventing cardiovascular diseases.
Excessive cholesterol in the bloodstream can lead to hypercholesterolemia, threatening arteries and cardiovascular health by causing atherosclerosis through fatty deposits. To address this, scientists have created a therapeutic tool that blocks the PCSK9 protein, which regulates low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, by binding to LDL receptors on cells and reducing their numbers, thereby elevating circulating LDL-C levels.
The innovative approach employs polypurine hairpins (PPRHs), single-stranded DNA molecules that bind to complementary sequences to inhibit gene transcription. Specifically, two PPRHs—HpE9 and HpE12—target exons 9 and 12 of the PCSK9 gene. "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," explains Professor Carles J. Ciudad from the University of Barcelona's Department of Biochemistry and Physiology. This binding prevents RNA polymerase or transcription factors from acting, silencing PCSK9 expression and boosting LDL receptor (LDLR) levels for better cholesterol absorption.
The study, led by Professors Carles J. Ciudad and Verònica Noé from the University of Barcelona's Faculty of Pharmacy and Food Sciences and Institute of Nanoscience and Nanotechnology (IN2UB), collaborated with Nathalie Pamir from the University of Oregon in Portland. Funded by Spain's Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH), the research was validated in HepG2 cells and transgenic mice expressing human PCSK9. In cells, HpE12 reduced PCSK9 RNA by 74% and protein by 87%. In mice, a single HpE12 injection lowered plasma PCSK9 by 50% and cholesterol by 47% on the third day. "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," states Professor Verònica Noé.
Compared to existing PCSK9 inhibitors like siRNAs (e.g., Inclisiran) or monoclonal antibodies (e.g., evolocumab, alirocumab), PPRHs offer advantages including low synthesis cost, stability, lack of immunogenicity, and avoidance of statin-related side effects such as myopathies. The experts conclude that this PPRH-based method provides a promising, statin-free option for cholesterol control and cardiovascular protection.