Engineered derivatives of Hepatocyte Growth Factor in the prevention and treatment of liver disease. (360G-Wellcome-081377_Z_06_Z)

In experimental systems Hepatocyte Growth Factor/scatter factor induces hepatocyte proliferation and prevents apoptosis; in animal models (HGF/sf) can prevent and reverse acute and chronic liver damage. Native HGF/sf is a large complex protein; we have engineered truncated forms which are smaller, and potentially much more attractive molecules to develop for therapeutic purposes, reflecting their less complex tertiary structure and ease of production. We shall therefore characterise their effe cts in two sets of studies. Firstly we will assess the activity of wild-type and engineered forms of hgf/sf on human liver cells in order to confirm that they elicit the same biological responses as they do on rodent cells, and identify the most active engineered form. Secondly we will explore the activity of the proteins in established and validated pre-clinical models of (i) acute liver failure, (ii) chronic, progressive liver disease and, (iii) survival and recovery from large surgical resec tion. The two sets of studies should provide the data necessary and sufficient for subsequent clinical studies in patients with acute liver failure, advanced cirrhosis and in patients undergoing large liver surgery, opening the prospect of taking hgf/sf into the clinic.