Direct-to-Phase II SBIR: Validation of targets for therapeutic intervention in NASH. ABSTRACT Non-alcoholic steatohepatitis (NASH), is part of the progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), a public health crisis affecting 75% of type 2 diabetics and 95% 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 levels of insulin (~10,000X in vivo) and glucose (~3X in vivo) to sustain viability. This, along with the use of mouse models that do not mimic human disease pathogenesis, helps explain the unfocused target landscape in NASH with over 40 drugs in preclinical/clinical development without consensus on optimal human targets, and resulting high failure rates. HemoShear Therapeutics is a biotechnology company that utilizes a patented technology to recreate human liver diseases. In a previous SBIR (1R4DK100136), we developed a multi-cellular NASH system that recapitulates key elements of the disease, including similar transcriptomic and metabolomics signatures observed clinically in human biopsies from NASH patients. This system has been accepted for publication in a high-impact journal (JCI Insight), and in multiple presentations at AASLD Liver Meetings, receiving three Presidential Awards. More than 20 compounds, including many currently in clinical trials, were evaluated in this NASH system using a combination of ?omics and functional endpoints to create a rich data-set for target identification. Using this dataset, we have performed a gap analysis to gain a deeper understanding of the relative strengths and weaknesses of the current industry pipeline and importantly identified three promising targets that require further validation for future development of therapies for NASH. The purpose of this Direct- to-Phase II SBIR is to further validate these targets in the HemoShear NASH system and in an animal model of NASH and to develop the functional target assays necessary to launch a small molecule drug discovery program. !
Direct-to-Phase II: Validation of targets for therapeutic intervention in NASH. NARRATIVE Non-alcoholic steatohepatitis (NASH), is part of the progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), a public health crisis affecting 75% of type 2 diabetics and 95% of obese individuals. Mouse models do not mimic human disease pathogenesis, which may explain the unfocused target landscape in NASH with over 40 drugs in preclinical/clinical development without consensus on optimal human targets, and resulting high failure rates. HemoShear Therapeutics is a biotechnology company that utilized a patented technology to develop a multi-cellular NASH system that recapitulates key elements of the disease, including responses observed clinically in NASH patients. More than 20 compounds were evaluated in this NASH system to create a rich data-set for novel target identification. Using this dataset, we identified three promising targets. The purpose of this Direct-to-Phase II SBIR is to further validate these targets and develop functional target assays necessary to launch a small molecule drug discovery program. !
