Recombinetics, Inc. — Department of Health and Human Services SBIR Phase I: 100

Description

PROJECT SUMMARY Nonalcoholic fatty liver disease NAFLD is the accumulation of fat in liver cells that advance to the more severe form called nonalcoholic steatohepatitis NASH characterized by inflammation scarring cirrhosis liver failure and hepatocellular carcinoma warranting liver transplant Despite the profound economic and health impacts of NAFLD NASH little progress has been made in the management of patients with these severe clinical conditions While weight loss and anti diabetic medications are cornerstones of treatment there is considerable interest in identifying more direct therapeutic interventions Such developments are currently hampered by lack of an animal model with high physiologic fidelity to the human condition particularly with respect to the development of fibrosis immune evasion and metabolic syndrome features that define human NASH To that end we propose to utilize our state of the art gene editing platform to engineer Ossabaw swine with the most potent mutation associated with human NASH PNPLA I M We hypothesize that Ossabaw pigs carrying PNPLA I M alleles will develop histologically severe liver injury typical of human NASH along with metabolic syndrome with atherogenic dietary challenge Founder animals will be subject to routine clinical chemistry lipidomic workups and histopathological examinations sufficient to qualify fidelity of the model Success in this endeavor would warrant a Phase II submission wherein the impact of the PNPLA I M mutation could be more extensively investigated namely through more detailed imaging histologic cytokine and immune cell phenotyping In addition to state of the art gene editing platform with expertise of Drs Melkamu Veterinary Physiology and Carlson Animal biotechnology from Recombinetics we have engaged as co investigators experts in clinical and pathophysiological aspects of NASH in human and in swine nutritional model Drs Naga Chalasani and Tiebing Liang from Indiana University biochemical aspects of NASH from Vanderbilt University Drs Gerry Oandapos Sullivan a local veterinary pathologist from the University of Minnesota and Dr Pierre Bedossa a world renown expert in scoring liver histopathology will serve as consultants A reliable large animal model of will have tremendous impact on industry and academic research to develop and test new drugs and novel therapeutic approaches to treat this disease and expertise in Dr Charles Robb Flynn NASHPROJECT NARRATIVE This SBIR brings together expertise in gene editing clinical hepatology and lipid metabolism to develop a swine model of nonalcoholic fatty liver disease NAFLD or nonalcoholic steatohepatitis NASH by joining genetic and environmental risk factors We use precise gene editing technology to seamlessly introduce PNPLA I M the strongest associated mutation with NASH onset and severity into the Ossabaw pig that already has natural propensity to obesity and metabolic syndrome There is still no cure for NAFLD NASH Liver transplantation is the only treatment for advanced cirrhosis with liver failure We propose that this unique large animal model will mimic the human condition and accelerate the development of new diagnostic biomarkers and novel therapeutic targets of NAFLD NASH