Intraductal gene therapy for liver cirrhosis. - Project Summary The liver is one of the most important organs for gene therapy of both inherited and acquired disorders. In non-fibrotic livers, the hepatocytes are accessible from the systemic blood circulation due to the fenestration of hepatic sinusoids. For this reason, most liver-directed gene therapy today is administered systemically, typically by intravenous injection. However, the systemic route of administration has several disadvantages. First, every organ is exposed to the gene therapy agent, leading to potential off-target effects. Second, the effective concentration of the vector is significantly diluted by the large blood volume. Finally, the normally patent sinusoidal fenestrations are closed in cirrhotic liver disease, limiting access to hepatocytes in fibrotic conditions. However, an alternative route of administration that potentially abrogates these limitations also exists. The liver is accessible via its biliary duct system and the use of this approach remains largely unexplored for gene therapy. In this application, we propose to systematically explore the intraductal route of administration for multiple gene therapy modalities. We have three lead hypotheses: 1) The biodistribution profile of gene therapy vectors will be improved by ductal injection and less off-target effects will be observed; 2) The effective dose of the gene therapy agent will be significantly lower compared to systemic administration and 3) Efficient hepatic transduction can be achieved in liver cirrhosis. We will explore two important liver gene therapy modalities, testing rAAV in Aim 1 and RNA nanoparticles in Aim 2. The utility of the intraductal route will be tested by delivering IGF-1 to cirrhotic rats.
