2023-08-01 08:16:35
They have screened a collection of approximately 130,000 compounds and found a class of molecules that decreased apoB secretion and lowered cholesterol levels.
Researchers at the Medical University of South Carolina (United States) have developed a novel system to search for new therapeutic compounds that reduce the secretion of apolipoprotein B (apoB), the main protein component of the LDL particle, from liver cells.
In their work, published in the scientific journal ‘Communications Biology’, they have screened a collection of approximately 130,000 compounds and have found a class of molecules that decreased apoB secretion and lowered cholesterol levels. These molecules have the potential to offer a new treatment regimen for patients with familial hypercholesterolemia (FH).
FH is a genetic disorder that increases the risk of cardiovascular disease, due to increased levels of bad cholesterol in the blood. Normally, the low-density lipoprotein receptor (LDLR) binds to circulating cholesterol and delivers it to liver cells, where it is broken down.
However, in FH, the LDLR is mutated, so the liver cannot remove cholesterol as well, leading to hypercholesterolemia. According to the American Heart Association, approximately 1 in 200 adults carry the HF mutation.
Patients with high cholesterol are often prescribed statins. Statins lower cholesterol by increasing LDLR levels; however, its efficacy varies greatly from population to population, and patients with homozygous FH mutations are resistant to statin therapy because their LDLR gene is mutated.
To identify potential new therapies, the researchers created cells similar to the human liver from induced pluripotent stem cells (iPSCs). iPSCs are artificial stem cells derived from skin or blood cells. This technique allowed the team to produce large numbers of cells to analyze a vast library of chemical compounds. Using this model system, the team discovered a unique class of promising compounds for the treatment of FH. They found that apoB levels drop a lot when we deliver the drug to cells. “Cholesterol levels drop and so do triglycerides.“.
The team next tested these compounds in a preclinical mouse model. Surprisingly, however, these compounds were ineffective in the mouse. Closer examination of the mouse liver cells showed that they were resistant to the compounds, highlighting a key difference between a human cell model and a mouse model.
To overcome this obstacle, they used Avatar mice, that is, mice designed to grow a liver from human cells, instead of mouse cells.
This humanized mouse model is a powerful tool; the presence of the human-derived liver recapitulates the lipid profile observed in patients and thus represents a model for testing new therapies in a complex system. Compounds identified in the iPSC screen were also effective in this complex animal model.
In short, they created a powerful system for modeling complex diseases and testing new therapeutic compounds. The team identified a new class of compounds that effectively lower cholesterol, triglycerides, and apoB. More importantly, these drugs act independently of the LDLR pathway, which traditional therapies target, and offer a novel therapy for FH patients.
Although this work is promising, there is still work to be done. “Discovering the target of the drug and showing its mechanism of action is an absolute priority.“, the authors have commented.
Learning how the drug works is an essential next step and could identify other important proteins that other drugs could target. Another key question is how these compounds interact with conventional therapy, such as statins. The combination of these drugs could have a powerful cholesterol-lowering effect, by reducing both the cholesterol that is manufactured and the cholesterol that circulates in the body.. M.T.T./ L.D.B. (SyM)
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