Full Breakdown
DNA-Based Polypurine Hairpins Show Promise in Silencing PCSK9 to Lower Cholesterol
5/5/2026, 11:52:27 AM
Breakthrough Gene-Silencing Approach Targets PCSK9
Researchers at the University of Barcelona and the University of Oregon have engineered short DNA molecules—polypurine hairpins (PPRHs)—that bind the PCSK9 gene and block its transcription. Inhibiting PCSK9 raises hepatic LDL-receptor (LDLR) levels, enhancing removal of low-density lipoprotein cholesterol (LDL-C) from the bloodstream.
Scientific Background on PCSK9 and Cholesterol
PCSK9 attaches to LDLR on liver cells, promoting receptor degradation and limiting LDL-C clearance. Elevated PCSK9 correlates with higher LDL-C and increased cardiovascular risk. Existing PCSK9-targeted therapies include monoclonal antibodies (evolocumab, alirocumab) and the siRNA drug Inclisiran.
Key Researchers and Funding
The study was led by Professors Carles J. Ciudad and Verònica Noé at the University of Barcelona, with collaboration from Nathalie Pamir at the University of Oregon. Funding came from Spain’s Ministry of Science, Innovation and Universities (MICINN) and the U.S. National Institutes of Health (NIH).
Experimental Findings in Cells and Mice
Two PPRHs, HpE9 and HpE12, were evaluated in HepG2 liver cells and in transgenic mice expressing human PCSK9. HpE12 reduced PCSK9 RNA by 74 % and protein by 87 % in cells. A single injection in mice lowered plasma PCSK9 by 50 % and cholesterol by 47 % within three days, while increasing LDLR levels.
Potential Clinical Impact
PPRHs are chemically synthesized, offering low cost, stability and minimal immunogenicity. The authors note that, unlike statins, this approach should avoid myopathic side effects. If efficacy translates to humans, PPRHs could become a cheaper, safer alternative to PCSK9 antibodies and siRNA drugs. Human trials are required to confirm safety and effectiveness.
Official Statements & Responses
Professor Ciudad highlighted the precise binding of the hairpins to exon-specific polypyrimidine sequences, which blocks PCSK9 transcription. Professor Noé emphasized the rapid cholesterol reduction observed in mouse models and the broader advantages of PPRHs, including cost-effectiveness and lack of immune activation.
Verbatim Quotes
- “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,” — Carles J. Ciudad, Prof., University of Barcelona
- “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,” — Carles J. Ciudad, Prof., University of Barcelona
- “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.” — Verònica Noé, Prof., University of Barcelona
- “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,” — Verònica Noé, Prof., University of Barcelona
What’s Next
The team plans dose-response studies in larger animals, followed by Phase I safety trials in humans to assess efficacy and tolerability.
