2023-09-06

The mouse equivalent of Lipigons drug candidate Lipisense^® has been tested in a disease model for atherosclerosis with remarkable results. Milena Schönke, PhD and Senior Researcher in Cardiometabolic Diseases and her team from Leiden University Medical Center in the Netherlands, presented the key findings from the study at the Scandinavian Society for Atherosclerosis (SSAR).

Milena Schönke, PhD and Senior Researcher in Cardiometabolic Diseases at Leiden University Medical Center in the Netherlands, has, in collaboration with Lipigon, studied the mouse equivalent of Lipisense^® in a disease model for atherosclerosis. The promising results were presented at the Scandinavian Society for Atherosclerosis (SSAR) conference in Denmark in March.

– We found that the drug candidate very effectively reduced the blood levels of cholesterol and triglycerides in mice. This led to a remarkable 86 percent size reduction of atherosclerotic lesions, the fatty plaques in the arteries that cause cardiovascular diseases, says Milena Schönke.

This improvement of blood lipid levels with the inhibition of Angptl4 was caused by an increased uptake of lipids from the blood by brown adipose tissue, a small fat depot that burns energy rather than just storing it, and a reduced secretion of lipids by the liver.

This study was performed in the “gold standard” Leiden mouse model. Why is this model highly considered?

– The anti-Angptl4 antisense oligonucleotide (ASO) was tested in mice that are genetically modified to have a “humanised” lipid metabolism and that are, therefore, prone to cardiovascular diseases. At the same time, they also respond to lipid-lowering drugs commonly prescribed in the clinic, like statins, which other disease models don’t.

Regular lab mice have a very good metabolism and do not develop these diseases on their own, so it was important that the mouse strain in the study responded to a diet with a lot of fat and cholesterol as humans do.

Milena Schönke was surprised that Angptl4 outperformed the established target Angptl3 in the study.

– After all, Angptl4 is also present in several other tissues in mice, so we did not necessarily expect the liver-specific inhibition of Angptl4 to be as effective in lipid reduction as the inhibition of Angptl3, which is only present in the liver.

Data from the study also showed that Angptl4 ASO treatment particularly lowered plasma triglycerides during fasting, while Angptl3 inhibition reduced plasma triglyceride levels just after meals.

– This suggests that a combination of both treatments might actually work best, says Milena Schönke.

What implications do you think your data will have on the research field of atherosclerosis and future clinical practice?

– Our data clearly shows that liver-specific silencing of ANGPTL4 with an ASO is a very promising approach to treating cardiovascular diseases. The liver is such a central organ in regulating lipid metabolism in the whole body that we will hopefully soon see more drug candidates emerging that target the liver to improve cardiovascular diseases, fatty liver diseases and type 2 diabetes. Perhaps all at the same time.

Lipid-lowering statins are some of the most prescribed drugs worldwide, often tolerated well by patients. However, not everybody tolerates them, and there are still over 17 million deaths yearly from cardiovascular diseases.

– This shows that we need better and more effective treatments, which is why the further clinical development of Lipisense^® is so exciting!

Milena Schönke and her colleagues collaborate with several companies using their humanised mouse model for cardiometabolic diseases and their experience in studying the development and treatment of these diseases. For example, with Eli Lilly on the concept of their new dual GIP and GLP-1 receptor agonist, with Astra Zeneca on FGF21 – and with Lipigon on the ANGPTL3/4 silencing.

– Our collaboration with Stefan and his team at Lipigon has been very nice; they are always eager to see and discuss our new data and trusted us entirely with setting the scientific course of this work.