A second product candidate, STNM04, which targets the distinct glycogene, G family #4, is in development for the treatment of liver cirrhosis (LC). LC represents the final common endpoint of virtually all chronic liver diseases, including chronic viral hepatitis, non-alcoholic steatohepatitis (NASH), and toxic damage. The prevalence of chronic liver disease and cirrhosis is currently at 5.5 million cases in the US. The economic impact of cirrhosis is considerable, estimated at $1.5 billion in direct costs in 2000. Current treatments for cirrhosis are limited to removing the causative agents (i.e., eradicating viral particles using interferon), but host tissue remodeling responses progress irrespective of their inducer. Liver transplantation is the only effective treatment for cirrhosis at present.
Stelic researchers discovered that G family #4-derived glycoprotein is up-regulated by hepatic stellate cells and provides fibrotic scaffolds to newly accumulating fibroblasts. In vitro, G family #4 is up-regulated by fibroblasts in response to profibrotic stimuli like TGF-β. STNM04 is designed to selectively target G family #4 mRNA and inhibit the expression of G family #4-derived glycoprotein at sites of injury. Pre-clinical data suggest that STNM04 depletes fibroblasts, leading to restoration of normal liver architecture. STNM04 is therefore a novel drug candidate focusing on hepatic stellate cells as well as fibroblasts in the liver.
Pre-clinical study of STNM04 in a murine model for LC.
Upper panels: Hepatic stellate cells and partly hepatocytes produce G family #4-derived glycoprotein (brown, arrowheads) and navigate the positioning of fibroblasts (red, arrow) along the fibrotic architecture. CV: central vein. Lower panels: Distribution of glycoprotein (brown) in LC model. Compared to control (left), STNM04 almost completely perturbs fibrotic architecture created by glycoprotein (right), followed by depletion of fibroblasts and excessive collagen.
