BEASTS-Novel Biomimetic Liver Platform for Enabling ALD Researchers

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PROJECT SUMMARY Alcoholic liver disease (ALD) is one of the major causes of morbidity and mortality in the world. Significant challenges remain for developing preventive or curative approaches targeting ALD. No effective treatments for ALD currently exist but for reducing alcohol consumption or liver transplantation. The current paucity of clinically relevant experimental models impedes any effort to identify ALD prognostic indicators and potential effective treatment options. It has been challenging to develop an animal model that exhibits severe alcohol- induced injury such as fibrosis or cirrhosis. Biomimetic in vitro models are urgently needed to allow both investigation of the mechanisms of liver fibrosis and higher-throughput screening of drugs and drug combinations that decrease liver fat accumulation and/or prevent the generation of a fibrotic reaction to steatosis. While some in vitro platforms have recently reported the development of more pathologically relevant liver models, their methodology lacks both dynamic (mechanical) cues that might improve the model relevance and in situ bioanalysis capacity, limiting their possible integration with personalized drug screening. Also, though some of these platforms shown maintenance of several key hepatocyte differentiated function in vitro, none of these platforms have demonstrated alcohol dehydrogenase (ADH) and CYP2E1 expression/activity for sustained periods which are critical for alcohol metabolism and for studying ALD. This limitation is particularly noteworthy since these elements are critical to the development of ALD. The overall goal of Keshava Biosciences LLC is to develop a novel biomimetic liver model closely mimicking the hepatic environment in physiologic and pathological conditions enabled by microtechnology. Keshava Biosciences LLC in collaboration with Dr. Kidambi (CEO and bioengineer with expertise in biomimetic liver models) has pioneered the use of biomimetic “BEASTS (Bio-Engineered Adhesive Siloxane substrate with Tunable Stiffness)” platform, which enables preserving primary human hepatocytes (PHHs) including liver- specific synthetic functions (urea and albumin production; bile acid uptake), maintaining ADH and CYP2E1 activity for 10 days. BEASTS platform uniquely recreates the physiologic (2 kPa) and pathologic liver stiffness at various stages of ALD (8, 15, 25, 55 kPa) to allow mimicking fibrosis in ALD patients which is lacking in current animal models. The model will be optimized in 3 steps: optimization of the mechanical insult, optimization of the injury phenotype and optimization of the therapeutic effect of positive control compounds. These tools hold the promise of incremental clinical success in place of the status quo of total clinical failure. Ultimately, this disruptive technology will enable the rapid screening of pharmacological compounds for beneficial or detrimental effects on ALD and for the detection of pharmacogenetic interactions. This also aligns well with NIAAA interests- (i) Development and validation of tools, models, and technologies; (ii) Development of drug candidates for treating ALD.