Researchers at the University of Barcelona and University of Oregon have developed a genetic therapy that cuts dangerous cholesterol levels by nearly half, potentially offering patients a path away from statins and their muscle-related side effects.
The breakthrough centers on a protein called PCSK9, which acts as a gatekeeper for cholesterol removal from the bloodstream. By blocking this protein's production with specialized DNA molecules, the treatment lets cells absorb more cholesterol and reduces dangerous fatty buildup in arteries.
Led by Carles J. Ciudad and Verónica Noé at Barcelona's Faculty of Pharmacy and Food Sciences, the team designed molecules called polypurine hairpins (PPRHs) that bind to the PCSK9 gene and prevent it from being activated. The research, funded by Spain's Ministry of Science and the U.S. National Institutes of Health, appears in Biochemical Pharmacology.
In laboratory tests on human liver cells, one version of the treatment, called HpE12, slashed PCSK9 RNA by 74 percent and protein levels by 87 percent. When tested in genetically modified mice carrying the human PCSK9 gene, a single injection reduced cholesterol by 47 percent within three days.
The mechanism works at the genetic level. PCSK9 normally attaches to LDL receptors on cell surfaces, blocking the cells' ability to pull cholesterol from the blood. By suppressing PCSK9 production, the treatment increases the number of available receptors, dramatically improving cholesterol clearance.
Existing cholesterol drugs target PCSK9 through different approaches. Inclisiran uses RNA-silencing technology, while monoclonal antibodies like evolocumab and alirocumab directly block the protein. PPRHs may offer practical advantages: they are cheaper to manufacture, remain stable in the body, and don't trigger immune responses that could limit effectiveness.
More importantly for patients, researchers believe the DNA-based approach would avoid the muscle pain and weakness that plague many statin users, a side effect that causes some people to abandon cholesterol treatment entirely.
The findings are preliminary. The therapy has not yet moved into human trials, and real-world effectiveness remains unproven. Still, the results suggest a potentially cleaner option for the millions managing high cholesterol and cardiovascular risk.
Author Jessica Williams: "A DNA therapy that cuts cholesterol nearly in half without the muscle pain that derails statin compliance could genuinely reshape how millions manage heart disease risk."
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