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Potential New Therapies To Lower “Bad” Cholesterol Discovered

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A group of molecules with the potential to treat familial hypercholesterolemia, a genetic disease that causes high cholesterol levels, has been identified in a new study. The research, which showed the compounds successfully lowered cholesterol in lab-grown cells and mice with “human” livers, is published in Communications Biology.

Finding new treatments for high cholesterol

Familial hypercholesterolemia (FH) is a genetic disease that affects approximately 1 in 150 people. It causes abnormally high levels of low-density lipoprotein (LDL) – sometimes called “bad” cholesterol – in the blood.

In healthy people, LDL receptors bind to LDL to transport it to the liver where it is broken down. Those with FH have a mutation in the LDL receptor gene that limits its ability to bind and remove LDL.

The resulting buildup of “bad” cholesterol and lipid molecules (triglycerides) in the blood in turn increases the risk of heart disease or heart attacks. Most FH patients are treated with drugs to lower cholesterol, such as statins, but their efficacy varies throughout the population. For example, statins are relatively ineffective in people with two copies of the faulty FH gene.

In an effort to discover new therapeutics to treat FH, researchers from the Medical University of South Carolina (MUSC) developed a new system to screen thousands of drugs, identifying a group that that reduced the production of apolipoprotein B (apoB) – a major component of LDL molecules – and reduced cholesterol levels in laboratory models.

Success in humanized mouse models

The researchers, led by senior author Professor Stephan Duncan, began by screening drugs from the South Carolina Compound collection, comprised of approximately 130,000 compounds.

“Our approach is the original way of doing pharmacology – trying to find drugs that can fix the disease without knowing how it fixes it,” explained Duncan, professor and SmartState Endowed Chair in the Department of Regenerative Medicine and Cell Biology at MUSC. “You model the disease, and then you can screen drugs to find out which ones work. Then you can work out retrospectively how the drug functions.”

“The nice thing about that is you are starting off by knowing the drug can actually fix the problem you hope to fix,” he added.

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The researchers screened the drugs using human liver-like cells, created from induced pluripotent stem cells (iPSCs) – artificial stem cells derived from skin or blood. This technique allowed the team to produce large numbers of cells to screen such a substantial compound library, identifying a unique class of compounds that show promise for FH treatment.

“We found that apoB levels go way down when we give the cells the drug,” said Duncan. “Cholesterol levels go down. Triglyceride levels go down.”

However, when the team turned to the next logical step to test these compounds – administering them to laboratory mice – they discovered they were ineffective. Examination of liver cells from the mice showed that they were resistant to the compound’s mechanism of action, highlighting a key difference between human cells and mouse models.

Duncan and colleagues turned to so-called “avatar” mice to surmount this issue. These animals were engineered with livers that grow from human cells instead of their own: “We used a humanized mouse model – a mouse with ‘your’ liver in it,” Duncan described.

The human-derived livers present in these models were able to reproduce the blood lipids found in patients, providing a good basis as a model system to test these compounds – indeed, the team found that the compounds effective in iPSCs were also effective in the modified mice.

Potential as a combination therapy

Overall, the compounds identified by the team were effective across these model systems, and importantly they offer a potential novel therapy for FH patients that targets an alternative mechanism.

“Showing that you can use these human stem cells as a system to model disease, complete a drug discovery process and find a drug that could potentially be used to treat a patient – that is the epitome of personalized medicine,” said Duncan. “This shows there is a very feasible way to do drug discovery using a human system.”

Duncan highlights that there is still work to be done: “Finding what the drug target is and showing the mechanism of action is an absolute a priority,” he added. These drugs also have the potential to be combined with more conventional therapies such as statins for a dual approach that targets both cholesterol in the circulation and cholesterol production.

Reference: Liu JT, Doueiry C, Jiang Y lin, et al. A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B. Commun Biol. 2023;6(1):1-17. doi: 10.1038/s42003-023-04739-9

This article is a rework of a press release issued by Medical University of South Carolina. Material has been edited for length and content.