2021-05-27

Prof. Sander Kersten, scientific advisor to Lipigon, is one of Europe's leading researchers in molecular metabolism, investigating the role of specific proteins in the body's lipid metabolism. In this interview, he discusses the target protein ANGPTL4 in the antisense drug Lipisense^®, which is being developed to treat elevated blood lipids.

Sander Kersten is a professor of molecular nutrition at Wageningen University in the Netherlands and is also affiliated with the Department of Nutritional Sciences at Cornell University in the USA. His research focuses on how fat is processed and regulated in the body, with an emphasis on what happens in the liver and fat tissue, two organs crucial to the body's fat metabolism.

As a scientific advisor to Lipigon, Professor Kersten contributes his expertise regarding angiopoietin-like proteins (ANGPTL), including ANGPTL4, which is the target protein in the company's main project, Lipisense^®.

Angiopoietin-like proteins play a key role in several physiological processes

Angiopoietin-like proteins (ANGPTL) constitute a family of closely related proteins that play key roles in regulating various physiological processes, including fat metabolism, inflammation, and the formation of new blood vessels. They also appear to play a role in several disease mechanisms. Specific mutations in the genes coding for distinct ANGPTL proteins have been identified to cause, among other things, lipid disorders that can lead to illness.

You made the significant discovery of the protein ANGPTL4. Could you share your findings?

"I discovered this protein while trying to find new genes involved in human fat metabolism. I used a very laborious technique to separate DNA molecules. Several of them were sequenced, and one of them coded for ANGPTL4. At that time, I called it Fasting-Induced Adipose Factor but abandoned that name after it became clear that it was part of a family of proteins with similar functions.

When I first identified ANGPTL4, I had no idea what it could do, but further research led me to understand that the protein increased during fasting and was secreted into the blood. I then thought it could be quite promising. The real insight came when I studied disruptions in fat metabolism in genetically modified mice that produced extra amounts of ANGPTL4 and accumulated a lot of fat in their blood."

Lipigon's drug candidate Lipisense^® aims to significantly lower elevated triglyceride levels in the blood. This is achieved by blocking the protein ANGPTL4, which, in turn, increases the activity of lipoprotein lipase, an enzyme that breaks down triglycerides. Can you elaborate on the interplay between the enzyme and the protein?

"Many people have elevated fat levels in their blood. The reason can be genetic, environmental, or a combination of both. Lipoprotein lipase is an enzyme responsible for breaking down fat in the bloodstream. When this enzyme's performance is deficient, fat accumulates in the blood. Thus, boosting lipoprotein lipase activity to lower fat levels in the bloodstream is advantageous for many. ANGPTL4 regulates the activity of lipoprotein lipase. It acts as an inhibitor, raising fat levels in the blood. From a therapeutic perspective, it makes sense to inhibit ANGPTL4."

Individuals suffering from conditions like SHTG (severe hypertriglyceridemia) and FCS (familial chylomicronemia syndrome) have significantly elevated blood triglyceride levels. In your opinion, what are the most effective treatment approaches for these conditions?

"In cases of SHTG and FCS, triglyceride breakdown is severely compromised due to poor functioning of lipoprotein lipase. Fortunately, methods are available to enhance lipoprotein lipase activity, thereby lowering triglyceride levels. One of the most effective strategies involves inhibiting angiopoietin-like proteins. This should be the focal point of treatment approaches for SHTG and FCS."

Lipisense^® is based on antisense technology (ASO) and aims to knock out the target protein before it is formed in the liver. What is your view of ASO in inhibiting a target protein like ANGPTL4?

"I think ASO is a highly promising technology for diseases related to disturbances in the body's fat metabolism. By blocking ANGPTL4, lipoprotein lipase's activity is enhanced, leading to lower triglyceride levels in the blood. A general inactivation of ANGPTL4 effectively lowers levels but also has side effects. However, by specifically inactivating ANGPTL4 in the liver, as Lipigon does, levels can likely be reduced without side effects."

Are there other potential diseases for which an ANGPTL4-targeted treatment would be suitable?

"ANGPTL4 has been linked to other diseases, especially cancer metastases, where the protein has been attributed a role in both increasing and decreasing the tumor's tendency to create metastases."

Read more: What are lipids and lipid-related diseases?

Read more about Lipigon's projects:

P1 Lipisense
P2 Lipodystrophy
P3 Dyslipidemia
P4 CAP