The Best Path Forward for Treating NASH: Stellate Cells vs Macrophages?

The emergence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as global health threats, along with the progression to NASH cirrhosis has brought cirrhosis back into focus as a large, unmet medical need. Much of this focus has been on preventing the development of NASH cirrhosis, but now there are also efforts to find treatments for those who have progressed to NASH cirrhosis. There are numerous pathways that are being explored as possible treatments.

Today, I want to focus on two of the most “popular” — if I can use that term — targets to drug development in NASH and NASH cirrhosis: Stellate cells and macrophages.

Those of us who saw cirrhosis patients in the 1980s knew that cirrhosis involved a massive invasion of the liver by a particular type of immune cell called macrophages, which is one type of cell known colloquially as “white blood cells.” Physicians knew that macrophages were heavily involved in cirrhosis because you could measure the inflammatory syndrome they created in cirrhotic patients. It was a characteristic of cirrhosis, but there wasn’t much we could do about it at the time.

Another characteristic of cirrhosis is liver fibrosis or scarring. This is caused by the build-up of scar tissue in and around liver cells in response to inflammation. Here, liver stellate cells play a central role in driving the deposition of this extracellular fibrous matrix.

It might seem natural, I suppose, to target stellate cells as a way to prevent fibrosis. If you can disrupt the complex cellular signals that cause stellate cells to trigger the development of scar tissue, you can theoretically stop the progression to NASH and NASH cirrhosis.

Unfortunately, development efforts for anti-fibrotic drugs targeting stellate cells have failed. Is that because stellate cells are not as important in the fibrotic process as we think, or is it simply because it is difficult to deliver potential medicines to the stellate cells?

It is hard to tell at this point, but not being able to deliver a drug successfully to the place where it is needed is a common problem in drug development. The work in the laboratory makes a potential drug seem like the perfect therapy for an intractable skin condition, but if it can’t be absorbed through the skin, then it will fail as a medicine meant to be applied to the skin.

Another approach to developing therapies for NASH and NASH cirrhosis is to target macrophages, which, as research has shown, also play a vital role in the development of NASH.

A normal liver contains a special class of white blood cells called resident macrophages, which can be identified under a microscope. They are an essential part of the liver. They are known as Kupffer cells, after the name of the German pathologist who discovered them.

Macrophages, of course, are found throughout the body, not just in the liver. As the name indicates, they are big cells (macro) that eat things (phage). Macrophages have two main functions: they are first a factory of protein synthesis, and secondly, they are garbage trucks. They are usually in a quiescent state, because they don’t have a lot of work to do when everything is working smoothly in the body.

Macrophages activate in response to injury or infection, and this is when they begin to secrete and gulp things. The secretions are cytokines and other proteins that promote inflammation, part of the body’s immune response. The gulping serves to clean the affected area. Anything that doesn’t look quite right, whether it’s a small molecule or even a cell, will be gulped by a macrophage and then digested. Macrophages are a very important part of the immune system.

When there is a problem in the liver, the Kupffer cells that are resident in the liver are not enough to do the job. They issue a chemical signal that attracts other macrophages to join the fight. All these cells are made in the bone marrow, and are there called monocytes. They migrate through the blood and transform themselves into macrophages in the liver.

In cirrhosis of the liver, there is a massive inflammation, and there is a massive invasion of the liver by macrophages. These macrophages are not residents, instead, they are circulating. Cirrhosis is characterized by a very large population of macrophages, and they are all trying to clean the liver of all the cirrhotic damage, but their actions and the resulting inflammation cause further damage to the hepatocytes that enable the liver to do its job.

If you have a drug that can tame down macrophages, it will also potentially tame down inflammation. This is important, because inflammation in the human body is the main factor for fibrosis, so any tissue that is chronically inflamed will eventually transform into fibrotic tissue. It happens in the kidneys, heart, lungs, liver, and even skin. If you tame inflammation, then you will tame fibrosis.

Macrophages initiate the development of fibrosis by producing galectin-3, a protein that is essential for the formation of scar tissue. Now, scar tissue is essential for repairing acute injuries, but when it builds up in response to chronic inflammation, it is not good.

Galectin-3 is the molecule that glues all the actors of inflammation, all the cells, together, to produce inflammation which results in fibrosis. Galectin-3 builds a structure for creating a fibrotic environment. If you can inhibit galectin-3, the idea is that you break down the fibrosis chain and avoid the formation of what some people have called the ”Galectin-3 fibrosone.”

Research is being done on a new molecule called belapectin, which acts as a galectin-3 inhibitor and might be useful as a therapy for NASH cirrhosis. Following the experience with treatment targeting stellate cells though, the key question is: can the belapectin be delivered to problem areas of the liver? This is where the characteristics of macrophages come in.

Belapectin is a large molecule made of carbohydrate chains, and the macrophages causing damage in the liver recognize it as a foreign substance and begin gulping it. When belapectin is gulped by macrophages, it stays in these cells for a long period of time. This puts a potential galectin-3 inhibitor smack in the middle of a macrophage, the cell most responsible for the production of galectin-3. Those macrophages causing havoc in the liver effectively become partners for delivering the belapectin galectin-3 inhibitor right where it is most needed.

There is good science supporting this method of action:

• Macrophages are involved in cirrhosis
• Galectin-3 is an integral part of the cycle of transforming inflammation into scar tissue: this is the galectin-3 fibrosone
• Macrophages are the primary producers of galectin-3
• Belapectin binds to galectin-3 and inhibits its function
• Belapectin is gulped by macrophages
• Belapectin resides in macrophages, and macrophages are in the liver

Galectin Therapeutics’ NAVIGATE Study is a Phase 2b/3 clinical trial that is currently underway to test whether this interplay between the macrophages and belapectin, a galectin-3 inhibitor, results in clinical benefit for NASH cirrhosis patients. The results from an earlier Phase 2 study are encouraging: belapectin prevented the development of esophageal varices in patients with compensated NASH cirrhosis. This is important because bleeding from varices is the cause of death for a third of NASH cirrhosis patients.

A successful trial will prove not only that inhibiting galectin-3 is of benefit in treating NASH cirrhosis, it will also confirm that macrophages are an effective target for delivering therapies for liver disease.