A new experimental therapy based on DNA has shown potential in significantly lowering cholesterol levels in mice, according to a study by researchers from the University of Barcelona and the University of Oregon. The treatment focuses on PCSK9, a protein that plays a key role in regulating levels of low-density lipoprotein cholesterol (LDL-C), commonly known as "bad" cholesterol. High levels of LDL-C can lead to the buildup of fatty deposits in arteries, increasing the risk of atherosclerosis, a condition that can cause heart attacks and strokes. By reducing PCSK9, the therapy allows cells to remove more cholesterol from the bloodstream. The researchers used a type of DNA molecule called polypurine hairpins (PPRHs), which are short, single-stranded DNA strands designed to interfere with specific genes. Two versions of PPRHs, named HpE9 and HpE12, were tested in the study. Both were effective at reducing PCSK9 RNA and protein levels while increasing LDLR, a receptor that helps cells take up LDL cholesterol. The mechanism involves one part of each PPRH binding to specific sections of the PCSK9 gene, which disrupts the process of gene transcription. This interference can either block the enzyme responsible for copying DNA into RNA or prevent other proteins from interacting with the DNA. The researchers tested the treatment in mice that had been genetically modified to express the human version of the PCSK9 gene. The most effective result came from HpE12, which, after a single injection, reduced plasma PCSK9 levels by 50% and cholesterol levels by 47% within three days. These results suggest that using PPRHs to suppress PCSK9 could increase the availability of LDL receptors in cells, helping them remove more cholesterol from the blood and potentially slowing the development of arterial plaque. PPRHs, especially HpE12, offer several advantages as potential therapies. They are relatively inexpensive to produce, stable, and less likely to trigger an immune response compared to other treatments. Researchers believe that PPRHs could provide an alternative method for targeting PCSK9, which is already a focus of several existing cholesterol-lowering treatments. These include gene-silencing techniques using small interfering RNAs (siRNAs), antisense oligonucleotides, and the CRISPR gene-editing tool. For example, Inclisiran is an siRNA-based drug that reduces PCSK9 production, while monoclonal antibodies like evolocumab and alirocumab target the protein directly. If further studies in humans confirm the promising results seen in mice, PPRHs could become a new tool in the arsenal of therapies aimed at lowering LDL cholesterol and improving cardiovascular health. The research was led by Carles J. Ciudad and Verònica Noé from the University of Barcelona, along with Nathalie Pamir from the University of Oregon. The work was supported by funding from the Spanish Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH). The findings were published in the journal Biochemical Pharmacology.