Molecule Shows Promise for MASH, Endometriosis, and Other Chronic Diseases

Macrophages are the first line of defense of the immune system, helping fight infections and keeping tissues healthy. But in the context of some chronic diseases, these immune cells undergo changes and become pathogenic, helping drive disease and creating inflammation.

Targeting these disease-induced macrophages without also killing off the protective ones has been challenging. But researchers have now discovered markers that are unique to pathogenic macrophages and have developed a molecule that can specifically eliminate them.

They published their findings in the Journal of Clinical Investigation.

While the team conducted these studies specifically in models of the liver disease known as metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis, the researchers are optimistic that the small molecule, called Bobcat339, and its future derivatives, could be a one-size-fits-all approach that treats a multitude of chronic diseases associated with inflammation.

“We have found a very potent target associated with multiple chronic diseases, and we have a way to treat this target with Bobcat339,” says Yingqun Huang, MD, PhD, professor of obstetrics, gynecology & reproductive sciences at Yale School of Medicine and the study’s principal investigator. “And we are in the process of identifying even more potent molecules to treat these diseases.”

Across different chronic diseases, the affected part of the body often experiences cellular and molecular changes. Known as the disease microenvironment, this is what triggers healthy macrophages to become pathogenic.

For the study, the researchers exposed healthy human and mouse macrophages to factors that mimicked different disease microenvironments. Doing so turned the macrophages pathogenic. Next, the researchers analyzed gene expression in these macrophages and found that the disease microenvironment upregulated expression of a gene called TET3. This in turn induced further changes that fueled inflammation and suppressed the immune system.

These downstream changes, however, also made the macrophages susceptible to Bobcat339. While Bobcat339 is designed to degrade TET3 protein—the product of the TET3 gene—overexpression of TET3 alone is not enough to make the macrophages vulnerable to Bobcat339; the additional changes triggered by the disease environment are necessary for Bobcat339 to work.

“Factors in the disease microenvironment not only induce TET3 overexpression in the macrophages but also change other genes. That creates a state in which the macrophages—which we call TET3-overexpressing macrophages—become sensitive to TET3 protein degradation,” Huang explains. “It’s a very specific population of macrophages—disease macrophages.”

To the researchers, that suggested Bobcat339 should be able to target macrophages that are driving disease and spare healthy, protective macrophages. And additional experiments showed the molecule was capable of doing exactly that.

The researchers found that Bobcat339 was successfully able to target and kill pathogenic macrophages without harming healthy ones. The team also tested the molecule in mouse models of MASH, NSCLC, and endometriosis. Across these three models, Bobcat339 decreased liver damage and liver fibrosis, reduced tumors and increased survival, and shrunk endometriotic lesions.

Many individuals living with chronic diseases today still have few effective treatment options. In the future, Bobcat339 or its derivatives could be a new tool for helping patients manage their conditions.

To assess the safety of Bobcat339, Huang’s team is conducting rigorous toxicity studies in animal models. So far, the molecule’s safety profile has been promising, she says. “If it continues to not show bad side effects, we can hopefully move onto human trials.”