Targeting Nash progression with STAM, the World's first mouse model of liver cancer induction from NASH

Non-alcoholic steatohepatitis (NASH) has emerged as a critical unmet need, with rising prevalence and no approved treatments yet. It is characterized by progressive liver inflammation and damage that can eventually lead to cirrhosis and hepatocellular carcinoma (HCC). However, the lack of predictive preclinical models that reflect the full spectrum of human NASH has hampered drug development efforts.?

Most existing dietary or genetic rodent models involve an additional “second hit” with chemicals like carbon tetrachloride to precipitate liver injury. While useful for understanding disease mechanisms, these models do not exhibit the characteristic step-wise progression from simple steatosis to steatohepatitis, fibrosis, and HCC as seen in patients. They also do not develop metabolic features of insulin resistance and dyslipidemia integral to human NASH pathogenesis.

The STAM mouse model developed by SMC Laboratories overcomes these limitations and is gaining traction as a translational model for NASH drug discovery. It involves a combination of streptozotocin injection in 2-day-old neonatal mice to induce insulin resistance, followed by 4 weeks of high-fat diet feeding starting at week 4. This produces the key metabolic drivers of human NASH.

By week 6, STAM mice uniformly develop steatosis, similar to human non-alcoholic fatty liver disease (NAFLD). This progresses to definite steatohepatitis by week 8, bridging fibrosis by weeks 10-12, and visible tumor nodules around week 16. By week 20, all STAM mice exhibit a large tumor burden constituting HCC, thereby capturing the entire spectrum of NASH pathogenesis.?

Extensive multi-omics characterization and comparison to human NASH have been published. Key validating features include histological hallmarks like hepatocyte ballooning degeneration and pericellular fibrosis, elevated transaminases, dyslipidemia, gut barrier changes, and established circulating and tissue NASH biomarkers. The model has been commercialized for preclinical studies and used by over 40 pharmaceutical companies.

Importantly, the STAM model has demonstrated clinical predictivity. Compounds like vitamin E, pioglitazone, GLP-1 agonists, and SGLT2 inhibitors showing efficacy in human NASH trials have exhibited similar benefits in STAM mice. FXR agonists, which are progressing in late-stage NASH clinical trials, were first shown to attenuate steatohepatitis in this model. The model has supported over 15 IND applications.