Small molecule notch agonist as a therapeutic for liver disease in alagille syndrome

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Silphion Life Sciences, Inc., $304,630 on August 20, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop a small-molecule Notch agonist as a therapeutic treatment for liver disease in Alagille Syndrome.

Alagille Syndrome is an autosomal dominant disorder caused by reduced Notch signaling from loss-of-function mutations, primarily in the JAG1 gene and less frequently in NOTCH2. The disease causes bile duct paucity in the neonatal and postnatal liver, leading to cholestasis, liver failure, and death, with an estimated prevalence of 1 in 40,000 births and a 60 percent mortality rate by age 19 in patients with a native liver. No pharmacological treatments currently exist for the condition. The recipient is developing a validated small-molecule direct Notch receptor agonist that enhances Notch signaling across human and mouse cell lines and demonstrates efficacy after oral administration in mice. Prior in vivo studies using an Alagille Syndrome zebrafish model showed that genetically restoring Notch signaling enables near-complete regeneration of lost liver duct cells.

Work is performed in San Diego, California with a period of performance from the award date through July 31, 2027.

Abstract

Alagille syndrome (algs) is an autosomal dominant disorder caused by a reduction in notch signaling, resulting from heterozygous loss-of-function mutations primarily in the notch ligand gene, JAG1, and less frequently in the notch receptor gene, NOTCH2 (N2). While algs is characterized by pleiotropic pathologies, hepatic and cardiovascular manifestations are most common and life threatening. In the algs liver, neonatal/postnatal bile duct paucity can lead to cholestasis and ultimately liver failure and death. With a prevalence estimated at ~1/40,000 births and a 60% mortality rate by age 19 for those with a native liver, algs urgently requires an effective treatment. This is underscored by the fact that there are currently no pharmacological approaches to correct algs pathologies and highlights both patient need as well as economic opportunity in this disease space. To address the root cause of this disorder -insufficient notch signaling- we propose to treat algs liver disease with a small molecule notch agonist. In support of this approach, our in vivo studies revealed that restoring notch signaling genetically in an algs zebrafish model allows for the near complete regeneration of lost liver duct cells. Moreover, spontaneous liver function improvement observed in some algs cases and all reported genetic modifiers of algs pathologies involve notch signaling. Therefore, therapeutic augmentation of notch signaling with a notch agonist is a simple and rational path to treat algs (1). We recently validated a new small molecule as a robust enhancer of notch signaling across a range of human and mouse cell lines, and in mice after oral administration. Extensive biological and mechanistic studies demonstrate that this compound is a direct notch receptor agonist and warrants its continued testing as a therapeutic approach to increase notch signaling to resolve hepatic defects in algs patients. We propose here to advance our preclinical investigation of our notch agonist compound by directly addressing its effects in primary human cholangiocytes and in mouse liver in vivo, each with algs mutations. Examining the effect of this notch agonist in human cholangiocytes and in mice with JAG1 mutations is necessary to determine its efficacy in preclinical, mammalian algs models. Critically, we will assess the pharmacological augmentation of notch signaling in the specific liver cell type that is impacted in the livers of human algs patients in vitro and in vivo. A rescue of these models will position this drug as a promising therapeutic approach for algs liver disease and help advance IT into IND studies, a necessary step toward clinic trials.