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New Oral Drug Lowers Cholesterol by 70%


Man Holding a Pill Medicine Drug

Cholesterol is a waxy substance found in the fats (lipids) in your blood. While your body needs cholesterol to build healthy cells, too much cholesterol can lead to a buildup of plaque in your arteries, increasing your risk of heart attack and stroke.

A team from University Hospitals and Case Western Reserve University has identified a small-molecule drug that effectively reduces cholesterol by 70% in animal models.

PCSK9 inhibitors are the second most common type of medication used to manage cholesterol levels, following statins. These drugs are highly effective at reducing excess cholesterol in the blood, but unlike statins, which can be taken orally, PCSK9 inhibitors must be injected. This can be a barrier to their use for some people.

A small-molecule drug that can be taken orally has been developed by researchers at University Hospitals and Case Western Reserve University School of Medicine. The drug has been shown to significantly reduce PCSK9 levels and lower cholesterol by 70% in animal models. These findings, published in the journal Cell Reports, represent a new approach to managing cholesterol and may also have implications for cancer treatments.

“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said Jonathan S. Stamler, MD, senior author, President, Harrington Discovery Institute at UH, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation, and Professor of Medicine and Biochemistry at UH and Case Western Reserve School of Medicine.

“Statins only lower cholesterol so far. This is a drug class that we think would represent a new way to lower cholesterol, a new way to hit PCSK9.”

Study Findings

Central to cholesterol regulation are LDL receptors, which sit at the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels. PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.

Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. In the new study, Stamler and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug display a 70% reduction in LDL “bad” cholesterol.

Beyond Cholesterol to Cancer

In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies.

“PCSK9 not only targets LDL receptors for degradation, but it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells,” said Stamler. “PCSK9 is effectively preventing your lymphocytes from recognizing cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to that need.”

Reference: “A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis” by Colin T. Stomberski, Nicholas M. Venetos, Hua-Lin Zhou, Zhaoxia Qian, Bryce R. Collison, Seth J. Field, Richard T. Premont and Jonathan S. Stamler, 25 October 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.111538





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