Genetic Liver-Targeted Diseases

Targeting the Liver.

Dicerna’s RNAi technology reflects a new approach in the development of therapies to treat rare, inherited diseases involving the liver and for other therapeutic areas in which the liver plays a key role such as rare diseases, chronic liver diseases, cardiovascular diseases and viral infectious diseases.

The GalXCTM RNAi technology platform is particularly well-suited for subcutaneous delivery of RNAi therapies to the liver, as hepatocytes (a type of liver cell) have a cell surface membrane receptor for the GalNAc sugars that are attached to GalXC compounds. This leads to effective internalization and access to the RNAi machinery within hepatocytes.

RNAi therapy is considered a rational approach to treating liver diseases such as primary hyperoxaluria type 1 (PH1), a severe, rare, genetic disease in which a single gene error in liver metabolism leads to high levels of oxalate in the urine, resulting in progressive and severe damage to the kidneys and other organs. RNAi may also emerge as a viable treatment for chronic liver diseases such as nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and progressive familial intrahepatic cholestasis (PFIC).

Although GalXC compounds have a remarkable affinity for hepatocytes, the potential utility of GalXC-derived RNAi therapy is not limited to diseases of the liver. Indeed, Dicerna has qualified dozens of disease-associated genes in clinical indications where we believe an RNAi-based inhibitor may provide substantial benefit to patients, providing expansive therapeutic opportunities. In addition, Dicerna has developed hits and/or optimized GalXC conjugate inhibitors against almost 40 of these qualified targets. These genetic targets span the therapeutic areas of rare diseases, chronic liver diseases, cardiovascular diseases and viral infectious diseases. The common thread among these targets is the expression of disease-associated genes in the liver. By silencing these genes, GalXC-based RNAi therapy may thus prove to be a valuable and practical therapeutic approach for a wide range of diseases.