Targeting ASK1 as a novel therapy to treat biliary atresia

Seal Rock Therapeutics, Inc., Seattle WA

Investigators

Abstract

Abstract Text The objective of this STTR proposal is to conduct efficacy and mechanistic studies of SRT-015 for the treatment of neonatal biliary atresia (BA) and to support an IND. Biliary atresia (BA) is the most common cause of neonatal cholestasis in early infancy and results from a fibro-inflammatory obstruction of extrahepatic bile ducts. Despite nearly uniform progression to end-stage cirrhosis, the variable response to surgical/medical treatment and rate of progression of disease suggest the existence of unrecognized biological processes that not only drive the disease phenotype but also provide untapped opportunities to develop newer therapeutic approaches. SRT-015 is a novel apoptosis signal-regulating kinase (ASK1) inhibitor with demonstrated efficacy in diverse models of liver disease. Here, we mined the murine extrahepatic bile duct and human liver transcriptome and built networks of ASK1 (MAP3K5) linked genes. The analytics identified proinflammatory gene signatures intricately linked to activation of ASK1 as well as components of the p38-MAPK axis as a potential therapeutic target to suppress inflammation and fibrosis. Using immunohistochemistry and liver specimens from human and experimental BA, we uncovered localization of ASK1 and p38-MAPK signals to proliferating cholangiocytes within areas of ductular reaction and immune cell infiltrations. These data form the foundation for the preclinical studies proposed in two inter-related aims. In Aim 1, we will establish the dosing schedule and optimal therapeutic dose of SRT-015 in preclinical models of bile duct cholangiopathy and liver fibrosis to achieve remission from cholestasis and improved survival with native liver. We will use the rhesus rotavirus (RRV)-induced neonatal mouse models of extrahepatic bile duct disease and liver fibrosis that recapitulate BA patient phenotypes. The minimum efficacious QD or QOD dose to attenuate jaundice, cholestasis markers, improve survival with native liver, and reduce liver fibrosis will be identified using three dose levels of SRT-015. Safety will be determined by observing for adverse effects. In Aim 2, we will perform detailed evaluation of the pharmacotherapeutic efficacy and mechanisms of SRT-015 to block injury and obstruction of the extrahepatic bile ducts and liver fibrosis at early and established disease stages. This approach aims to examine the potential benefits of SRT-015 in early stages of bile duct injury and inflammation, as well as established biliary disease and liver fibrosis. We will evaluate biomarkers, histology, liver immune cell phenotyping, and levels of gene expressions to interrogate the mechanisms. Our work will fully expand the efficacy data for SRT-015 in correcting in vivo bile duct and liver pathologies, and attenuation of liver fibrosis, providing essential preclinical data for future clinical trials in infants and children with biliary atresia. Once approved, SRT-015 is anticipated to extend the time to or ideally prevent the need for liver transplantation and significantly improve the lives of patients with biliary atresia.