After statins, the next class of drugs for cholesterol management are PCSK9 inhibitors. These highly effective agents help the body remove excess cholesterol from the blood, but unlike statins, which are available as oral agents, PCSK9 inhibitors can only be administered by injection, creating barriers to their usage.
Now, a new study by researchers at University Hospitals (UH) and Case Western Reserve University School of Medicine describes an orally-administered small-molecule drug that reduces PCSK9 levels and lowers cholesterol in animal models of 70%. Posted in Cell reportsthe findings represent a previously unrecognized strategy for cholesterol management and may also impact cancer treatments.
“Cholesterol reduction is one of the most important therapies we have to prolong life and protect people against heart disease, which is still the number one cause of morbidity and mortality in the Western world,” Jonathan said. S. Stamler, MD, senior author, Chairman, 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 class of drugs that we believe would represent a new way to lower cholesterol, a new way to achieve PCSK9.”
Study results
Central to cholesterol regulation are LDL receptors, which sit on 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 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, thereby lowering cholesterol. They identify a small molecule drug that works to increase nitric oxide inactivation of PCSK9. Mice treated with the drug show a 70% reduction in “bad” LDL cholesterol.
Beyond Cholesterol to Cancer
In addition to impacting cholesterol metabolism, the findings may impact cancer patients, as emerging evidence suggests that targeting PCSK9 may improve the efficacy of cancer immunotherapies.
“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for cancer cell recognition,” Stamler said. “PCSK9 effectively blocks your lymphocytes from recognizing cancer cells. So if you inhibit PCSK9, you can enhance cancer surveillance in the body. There may one day be the opportunity to apply these new drugs to this need.
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Material provided by University Hospitals Cleveland Medical Center. Note: Content may be edited for style and length.