A novel approach to treat non alcoholic steatohepatitis NASH

Abstract The Specific Aim of this Phase I STTR proposal is to test the feasibility of treating non alcohol steatohepatitis NASH by increasing mitochondrial metabolism which is the main pathway for lipid catabolism in the liver NASH is a stage of non alcohol fatty liver disease NAFLD that has progressed to a pathological state NASH can lead to cirrhosis leading to liver failure or hepatocellular carcinoma NASH is especially common in those with other metabolic disorders such as obesity diabetes and or hyperlipidemia but also affects the healthy population About of the population in US has NAFLD with million instances of NASH diagnosed each year in the US with advanced fibrosis and about million individuals progressed to cirrhosis The primary treatment for NASH is lifestyle change However few patients remain adherent for extended periods of time No drugs have been approved by the FDA for treating NASH To address this need we are developing an siRNA based drug to treat NASH by increasing liver metabolism Fatty acids are transported to the liver where they are metabolized through beta oxidation coupled to the electron transport chain ETC in the mitochondria Increased mitochondrial respiratory activity in the liver could therefore speed up the degradation of fatty acids and prevent their accumulation in the liver A key regulator of the ECT is the MCJ protein MCJ DnaJC or Methylation Controlled J protein MCJ is a mitochondrial protein that reduces respiration dependent ATP levels We have demonstrated that removal of MCJ activity is safe and results in increased mitochondrial metabolism ATP production We have developed an siRNA formulation siMCJ that effectively removes mouse MCJ in the liver Using this formulation we have shown in two mouse models that we can reverse or prevent NASH pathologies siRNA has been validated as a drug for number of diseases including liver diseases with over clinical trials having been run thus validating the use of this therapeutic approach While our preliminary data are compelling thus far the studies were carried out at only one dose of siRNA and against the mouse MCJ protein Thus to show feasibility of our approach prior to carrying out IND enabling studies we must carry out a more robust feasibility study that includes demonstration of safety a dose effect relationship and efficacy of human siMCJ To this end we will carry out the following Tasks Task Evaluate efficacy and toxicity of mouse siMCJ in vivo using mouse models Task Evaluate efficacy human siMCJ in vivo using humanized liver mouse model KMT Mice Test of Feasibility We must observe findings in Task that are similar to those in the preliminary study section and we must observe a dose effect curve that can be fit to a standard Hill type or log logit analysis and that covers the EC point of the curve We must observe a TI therapeutic index of at least maximally effective dose MTD This TI would indicate a very safe dosing window since we use a maximally effective dose as the numerator Findings in Task must also be similar to the findings in the preliminary study section Narrative Non alcohol steatohepatitis NASH is a devastating disease for which there is no FDA approved treatment NASH is an advanced stage of non alcoholic fatty liver disease NAFLD that can lead to cirrhosis liver failure as well as hepatocellular carcinoma While the frequency of NASH is very high in those with other metabolic disorders such as obesity diabetes and or hyperlipidemia about of healthy population also has developed the first stage of the disease About million instances of NASH are diagnosed each year in the US with advanced fibrosis and about million individuals have progressed to cirrhosis This is a proposal to develop the first FDA approved treatment for NASH