New Gene Therapy Shows Promise in Lowering Cholesterol

Innovative Approach Targets PCSK9, Offering Potential Alternative to Statins

A groundbreaking new gene therapy utilizing polypurine hairpins (PPRHs) demonstrates significant potential in reducing cholesterol levels and combating cardiovascular disease. This approach offers a promising alternative to existing treatments like statins, which can cause debilitating muscle pain in some patients.

How Polypurine Hairpins Work

The therapy focuses on inhibiting the production of PCSK9, an enzyme that limits the number of LDL receptors available to clear cholesterol from the bloodstream. By reducing PCSK9 levels, more receptors are available, leading to increased cholesterol uptake by cells and a subsequent decrease in circulating cholesterol. Professor Carles J. Ciudad, from the Department of Biochemistry and Physiology, explains that “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.” This binding effectively disrupts gene transcription.

Promising Results in Animal Studies

Researchers have validated this technique in transgenic mice expressing the human PCSK9 gene. The results are compelling: a single injection of HpE12 reduced plasma PCSK9 levels by 50% and cholesterol levels by 47% within three days. Professor Verònica Noé noted that “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%.”

Cardiovascular disease remains the leading cause of death globally, accounting for an estimated 17.9 million deaths each year, according to the World Health Organization (WHO, 2024).

A New Generation of Cholesterol-Lowering Therapies

Current treatments for high cholesterol include statins, monoclonal antibodies like evolocumab and alirocumab, and siRNA agents such as Inclisiran. PPRHs, particularly HpE12, present several advantages over these existing options. They are relatively inexpensive to synthesize, demonstrate good stability, and are less likely to trigger an immune response. Importantly, this approach avoids the myopathy side effects often associated with statin therapy.

This innovative gene therapy represents a significant step forward in the fight against cardiovascular disease, offering a potentially safer and more effective way to manage cholesterol levels and improve patient outcomes. Further research and clinical trials will be crucial to fully evaluate its long-term efficacy and safety.

Reference: López-Aguilar E, Pacheco-Velázquez SC, Busquets MA, et al. Inhibition of PCSK9 with polypurine reverse hoogsteen hairpins: A novel gene therapy approach. Biochem Pharmacol. 2025;238:116976. doi: 10.1016/j.bcp.2025.116976