Breakthrough in Lipoprotein Research: New Compounds Found to Inhibit Apolipoprotein B Production

New study results from Medical University of South Carolina have shed light on the treatment of familial hypercholesterolemia (FH) patients. The research focused on identifying safer compounds for treating patients with homozygous LDLR gene mutations (hoFH). Using an iPSC-derived hepatocyte platform, scientists screened a set of 10,000 small molecules from a proprietary library of 130,000 compounds, revealing molecules that reduce the secretion of Apolipoprotein B from cultured hepatocytes and humanized livers in mice. These compounds are highly effective, do not cause abnormal lipid accumulation, and share a distinct chemical structure from known cholesterol-lowering drugs.

Key Takeaways:

• Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), leading to severe cardiovascular disease.
• Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are inefficient at treating hoFH patients due to side effects such as liver triglyceride accumulation and elevated liver enzyme levels.
• An iPSC-derived hepatocyte platform was used to screen 10,000 small molecules for compounds that reduce Apolipoprotein B secretion from hepatocytes.
• The screen revealed highly effective compounds that do not cause abnormal lipid accumulation and share a distinct chemical structure from known cholesterol-lowering drugs.
• These compounds have the potential to revolutionize the treatment of hoFH patients, providing a safer alternative to existing treatments.
• The research involved a team of scientists from Medical University of South Carolina, including Jui-Tung Liu, Caren Doueiry, Yu-lin Jiang, and others.

Statistics:

• 10,000 small molecules were screened using an iPSC-derived hepatocyte platform to identify compounds that inhibit Apolipoprotein B production.
• The screen was conducted from a proprietary library of 130,000 compounds.
• The compounds identified in the study have been found to be highly effective in reducing Apolipoprotein B secretion in both cultured hepatocytes and humanized livers in mice.
• The research has the potential to improve the lives of millions of people worldwide suffering from familial hypercholesterolemia (FH).

Sources:

• A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B. Communications Biology, 2023,6(1):1-17. (Communications Biology - http://www.nature.com/commsbio).