Validation of a human in vitro system of hepatic steatohepatitis

Phase II SBIR Validation of a human in vitro system of hepatic steatohepatitis ABSTRACT Non alcoholic steatohepatitis NASH is part of the progressive disease spectrum of non alcoholic fatty liver disease NAFLD a public health crisis affecting of type diabetics and of obese individuals Glucose and insulin regulated de novo lipogenesis in the liver a critical step in the disease process is severely compromised in cellular hepatocyte systems typically used for drug discovery and development due to dedifferentiation in vitro and the requirement for supra physiological high levels of insulin X in vivo and glucose X in vivo to sustain viability The consequent lack of insulin sensitivity and responsiveness challenges the relevance of disease and target biology limiting the confidence in target discoveries made using these systems This along with the use of mouse models that do not mimic human disease pathogenesis may explain the current landscape of over drugs for NASH in preclinical clinical development without any consensus on the optimal human targets This lack of human relevance drives high failure rates for this indication HemoShear Therapeutics is a biotechnology company that utilizes a patented technology to recreate human liver disease biology using human primary cells In our Phase I SBIR we developed a steatohepatitis system using hepatocytes cultured in more physiological levels of glucose and insulin Since our last submission we have further matured the liver system to include human stellate cells and macrophages in addition to hepatocytes The resulting disease model exhibits progressive steatohepatitic changes in response to a pathological milieu based on human disease risk factors and demonstrates the ability of the HemoShear liver system to assess the therapeutic efficacy and mechanisms of promising new drug candidates at clinically relevant concentrations The purpose of the Phase II SBIR is to validate the disease relevance of the HemoShear multi cellular model by benchmarking against clinical liver tissue samples from NASH patients and to evaluate the effect of a diverse set of pharmacological pathway inhibitors on each of the core biological pathways impacted by the NASH phenotype !Phase II SBIR Validation of a human in vitro system of hepatic steatohepatitis NARRATIVE Non alcoholic steatohepatitis NASH is part of the progressive disease spectrum of non alcoholic fatty liver disease NAFLD a public health crisis affecting of type diabetics and of obese individuals In vitro cell culture and in vivo mouse models of NAFLD NASH do not recapitulate the human disease and may explain the current landscape of over drugs for NASH in preclinical clinical development without any consensus on the optimal human targets This lack of human relevance drives high failure rates for this indication HemoShear Therapeutics is a biotechnology company that utilizes a patented technology to recreate human liver disease biology using human primary cells Our Phase I SBIR and subsequent studies developed a multi cellular steatohepatitis system that exhibits progressive steatohepatitic changes in response to a pathological milieu that demonstrates the ability to assess the therapeutic efficacy and mechanisms of promising new drug candidates The purpose of the Phase II SBIR is to validate the disease relevance of the HemoShear multi cellular model by benchmarking against clinical liver tissue samples from NASH patients and to evaluate the effect of a diverse set of pharmacological pathway inhibitors on each of the core biological pathways impacted by the NASH phenotype