MERTK Inhibition As a Catch-All Antifibrotic Strategy

A variant in the Mer tyrosine kinase (MERTK) gene has been identified by genome-wide association and candidate gene studies as a mediator of fibrosis across multiple liver diseases, including metabolic dysfunction-associated fatty liver disease (MAFLD) and viral hepatitis. Despite this strong genetic evidence, MERTK has not been explored as a potential therapeutic target for fibrotic disease in other organs.

That led a group of researchers from Australia to explore the possibility of a antifibrotic strategy that would inhibit the pathology in a number of organs. Their findings were published in Science Translational Medicine earlier this year and concluded that fibrosis could be treated by MERTK inhibition.

“The era of genomics has provided efficient pathways to clinical translation and drug development,” Mohammed Eslam, M.D., associate professor at Storr Liver Centre in Sydney University and lead author of the study, told Managed Healthcare Executive. “A genetics-driven approach has many advantages. First, nearly half of disease susceptibility and progression in MAFLD are heritable. Second, gene variants can suggest biologic causality and provide insights into human mechanistic pathways and human genetic evidence for a target can enhance the likelihood of success.”

By using mouse models of liver, kidney and lung fibrosis, genetic deletion of MERTK prevented fibrosis. Moreover, a pharmacologic inhibitor of MERTK reduced fibrosis in these models and in an additional mouse model of liver fibrosis. The researchers employed an array of methods to confirm this finding including RT-PCR, Western blot and immunohistochemistry.

“Previous reports suggest that targets with GWAS [genome-wide association studies] evidence have a twice higher probability of successful clinical development compared to those without such evidence,” Eslam said. “As proof-of-principle, successful targets can often be retrospectively substantiated by genome-wide significant variants. For example, the new lipid-lowering PCSK9-inhibitors were among the top GWAS-identified risk variants for blood lipids.”

The team observed that MERTK induces TGFβ expression itself. TGFβ is the archetypal pro-fibrotic cytokine.

“It is therefore not surprising that TGFβ inhibition has been extensively investigated as an antifibrotic,” Eslam said. “However, this approach is limited by off-target effects and more selective approaches are warranted. Our data suggest the existence of a fibrosis-promoting positive feedback loop between TGFβ and MERTK. These findings suggest that MERTK inhibitors could offer a novel approach for selective regulation of the fibrotic effect of TGFβ. Such a selective approach may avoid interfering with other TGFβ-regulated gene networks that are crucial for cell viability.”

Fibrosis is a common feature of chronic metabolic diseases. It has specific features but also shares common pathways across various organs. Thus, a better understanding of the molecular regulation of the fibrotic response is required to fast track the development of next-generation therapies.

“MERTK inhibitors could potentially offer a potent antifibrotic drugs for various diseases,” Eslam said. “Recently, novel MERTK inhibitors with different pharmacokinetic and selectivity properties have become available, with ongoing effort to improve the properties of these molecules. Moving forward, collaboration among various stakeholders is essential to initiate a Phase 1 clinical trial that will investigate the safety of MERTK inhibitors for the treatment of fibrotic diseases.”