BioCentury
ARTICLE | Distillery Therapeutics

Hepatic

December 5, 2018 1:30 PM UTC

Patient sample and mouse studies suggest inhibiting the Notch pathway components HES1, γ secretase, MAML1 and NCSTN could help treat NASH. In NASH patient liver tissue samples, hepatocyte levels of HES1 were higher than in samples from patients with simple steatosis or healthy volunteers. In a mouse model of NASH, hepatocyte-specific knockout of MAML1 or NCSTN decreased liver fibrosis compared with normal expression of MAML1 and NCSTN. Also in the model, a γ secretase inhibitor tool compound or a liver-selective antisense oligonucleotide (ASO) targeting γ secretase decreased body weight, adiposity and liver fibrosis compared with vehicle or a scrambled ASO, respectively. Next steps could include identifying and testing small molecule inhibitors of HES1, MAML1 and NCSTN in other models of NASH.

Pfizer Inc. and SpringWorks Therapeutics LLC have nirogacestat, a γ secretase inhibitor, in Phase II testing for bone cancer...