A new DNA-based treatment offers a powerful alternative to traditional cholesterol medications by blocking a protein that keeps bad cholesterol circulating in your blood. Researchers from the University of Barcelona and the University of Oregon have developed a therapy using specialized DNA molecules called polypurine hairpins (PPRHs) that can reduce bad cholesterol levels by 47% in a single injection, according to findings published in Biochemical Pharmacology. Unlike statins, which can cause muscle pain and other side effects, this approach works at the genetic level to help your body clear cholesterol more effectively.

How Does This New DNA Therapy Actually Work?

To understand this breakthrough, it helps to know what happens when cholesterol builds up in your arteries. A protein called PCSK9 (protein convertase subtilisin/kexin type 9) plays a central role in this process. Think of PCSK9 as a gatekeeper that prevents your cells from absorbing cholesterol from your bloodstream. When PCSK9 levels are high, fewer receptors are available on your cells to remove cholesterol, causing it to accumulate in your blood and form fatty plaques in your artery walls.

The new therapy uses polypurine hairpins to interrupt this process at the genetic level. These short DNA strands bind precisely to specific sequences in the PCSK9 gene and block it from being transcribed, or copied, into the protein. By suppressing PCSK9 production, the treatment allows cells to absorb more cholesterol from the bloodstream, reducing the amount circulating in your blood and limiting buildup in your arteries.

What Were the Actual Results in Testing?

The research team tested two specific polypurine hairpins, called HpE9 and HpE12, in laboratory-grown liver cells and in transgenic mice carrying the human PCSK9 gene. The results were striking. In liver cells, HpE12 decreased PCSK9 RNA levels by 74% and protein levels by 87%. In the mouse studies, a single injection of HpE12 reduced plasma PCSK9 levels by 50% and cholesterol levels by 47% on the third day after treatment.

"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," explained Verónica Noé, a researcher at the University of Barcelona's Faculty of Pharmacy and Food Sciences.

Verónica Noé, Faculty of Pharmacy and Food Sciences, University of Barcelona

These results are significant because they demonstrate that the therapy can achieve cholesterol reductions comparable to existing medications, but through a completely different mechanism that avoids the common side effects associated with statins.

How Does This Compare to Existing Cholesterol Treatments?

Several approaches already target PCSK9 to lower cholesterol. These include other gene-silencing technologies and monoclonal antibodies that are already in use clinically. However, polypurine hairpins may offer distinct advantages over these existing options:

• Cost of Production: PPRHs are less expensive to synthesize compared to other gene-silencing technologies and monoclonal antibodies currently on the market.
• Stability and Safety: These DNA molecules are stable and do not trigger an immune response in the body, meaning they lack immunogenicity, which can be a problem with some other treatments.
• Side Effect Profile: Unlike statin therapy, which can cause myopathies (muscle diseases) and other adverse effects, a PPRH-based approach would not lead to these complications.

Existing treatments like Inclisiran (an siRNA therapy) and monoclonal antibodies such as evolocumab and alirocumab are already helping patients lower cholesterol. However, the researchers behind this new approach believe PPRHs could provide a safer and more targeted option for people who cannot tolerate statins or who need additional cholesterol reduction.

What's the Next Step for This Treatment?

While the results in cells and animal models are promising, this therapy is still in early stages of development. The research was led by Carles J. Ciudad and Verónica Noé from the University of Barcelona's Faculty of Pharmacy and Food Sciences and the Institute of Nanoscience and Nanotechnology, working with Nathalie Pamir at the University of Oregon. The study was funded by the Spanish Ministry of Science, Innovation and Universities and the National Institutes of Health in the United States.

"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 researchers concluded.

Research team, University of Barcelona and University of Oregon

Before this therapy can reach patients, it will need to move through clinical trials in humans to confirm its safety and effectiveness. These trials will determine the optimal dosing, frequency of treatment, and long-term outcomes. If confirmed in further studies, this new strategy could provide a safer and more targeted way to lower cholesterol and reduce the risk of heart disease for millions of people who struggle with high cholesterol levels.

For now, people managing high cholesterol should continue working with their healthcare providers to find the treatment approach that works best for them. Whether through statins, other existing medications, or lifestyle changes, controlling cholesterol remains one of the most important steps in preventing heart disease and stroke.