Inhibition of the target protein ANGPTL4 lowers triglyceride and glucose levels in the blood, according to a new study conducted by Lipigon and its Dutch partners. Targeted treatment of the liver avoids known side effects that might otherwise occur if the whole organism is treated. The study, published in the Journal of Lipid Research, shows that silencing ANGPTL4, the target protein for Lipigons most advanced drug candidate Lipisense, lowers triglyceride and glucose levels in the blood in a mouse model.

Furthermore, the animals were protected from obesity and fatty liver. The results confirmed what was expected based on genetic data from humans. The study used an antisense oligonucleotide, ASO, to silence the target protein.

An ASO is a short DNA/RNA sequence that binds complementary to a genes mRNA and prevents the cells from making the protein. Lipigons drug candidate Lipisense is the same type of ASO targeting human ANGPTL4. The study also shows that the risk of lymphatic side effects is avoided by Lipisense being targeted and mainly absorbed in the liver.

Previous studies have shown that lymphatic side effects can be a problem if ANGPTL4 is eliminated throughout the body. Sander Kersten is one of Europes leading researchers in molecular metabolism and scientific advisor to Lipigon. The target protein in the study, ANGPTL4, is an inhibitor of the lipid-splitting enzyme lipoprotein lipase (LPL).

LPL is essential for fat regulation in the blood, where its primary function is to break down the triglycerides in the blood. By preventing the bodys production of ANGPTL4, lipoprotein lipase activity increases, and blood fats decrease. After four injections of ANGPTL4-ASO, ANGPTL4 levels were inhibited, leading to higher LPL levels and decreased triglyceride and glucose levels in the blood.

The researchers also measured lower cholesterol in total, lower LDL cholesterol, lower serum amyloid A, a marker for inflammation, and lower liver triglyceride levels. They saw no significant difference in the liver enzyme plasma alanine aminotransferase, suggesting that Lipisense is well tolerated in animals. These effects reflect those previously seen in humans with alterations in the ANGPTL4 gene, which is associated with a reduced waist-hip ratio, a reduced risk of type 2 diabetes, and coronary artery disease.