Liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) are devastating diseases affecting millions of people, with poor prognosis and few treatment options. Liver fibrosis develops from chronic liver injury, and its progression leads to cirrhosis, end stage liver disease, and liver failure. Advanced fibrosis is also a major risk factor for HCC. Liver fibrosis is reversible, so therapies that target fibrosis have the promise of preventing the progression of disease. There are currently no FDA-approved treatments that target the process of fibrosis and very limited options for medical management of HCC.
Several epigenetic factors are implicated in liver fibrosis and subsequent HCC, including chromatin remodeling and histone modifying complexes. In particular, amplification or over-expression of several epigenetic factors has been associated with dysregulated gene expression and poor prognosis in HCC. Accordingly, interventions that decrease expression levels of these proteins have been shown to reduce fibrosis and tumorigenicity in animal models of HCC. Here we propose to develop antisense oligos (ASOs) to specifically deplete selected epigenetic regulators. ASOs can be readily targeted to the liver, thus enabling a promising novel approach to deplete proteins selectively in this tissue, for targeted treatment or prevention of fibrosis, cirrhosis and HCC.
Funding
Funding Duration
July 1, 2022 - June 30, 2023