In some individuals with a common inherited condition that predisposes them to high cholesterol (familial hypercholesterolemia), lifestyle changes might not be enough to prevent early-onset heart disease. Medical intervention is usually needed to lower cholesterol in these patients, and statins are the first-line treatment of choice. However, these drugs can have unpleasant side effects and are not effective in all cases.
Recent evidence suggests that inhibitors of PCSK9, a liver enzyme involved in regulating cholesterol homeostasis, could provide an effective alternative or adjunct to statin therapy in high-risk hyper-cholesterolemic patients. Before PCSK9 inhibitors can be approved for widespread use, further research into PCSK9 function using suitable preclinical models is needed. Reported in Disease Models & Mechanisms, a research group used an innovative approach to develop unique patient cell-based models of PCSK9-driven hypercholesterolemia. These models can be used to explore the cellular role of PCSK9 in vitro and to test the efficacy of cholesterol-lowering agents.
The group isolated cells from patient urine samples, amplified them, reprogrammed them into iPSCs and finally instructed them to become liver cells. Using this approach, they demonstrate that the pathological features of inherited hypercholesterolemia caused by PCSK9 mutations can be reproduced in a Petri dish.
As proof-of-principle, the team showed that the liver cell models generated from iPSCs respond as expected to statin treatment. Intriguingly, cells derived from patients carrying a particular gain-of-function mutation in PCSK9 showed an enhanced response to statins, and this finding was validated in vivo. The approach described thus generates clinically relevant models of hypercholesterolemia that can be used to predict pharmacological responses, paving the way to personalize the treatment of high-risk patients.