In vivo antisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

Niemann-Pick type C (NPC) is a fatal autosomal recessive lipidosis that is characterized by lysosomal storage of cholesterol and glycosphingolipids. Patients exhibit prolonged neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration that generally result in death by the teen years. Most clinical cases are caused by mutations in the NPC1 gene. Current mouse models of NPC are not well suited for studying the liver disease due to the rapidly progressing neurological disease. To facilitate study of NPC-associated liver dysfunction, we have developed a novel mouse model using antisense oligonucleotides to ablate NPC1 expression primarily in the liver. Here, we show that the NPC1 knockdown leads to a liver disease phenotype similar to that of patients with NPC and the NPC(nih) mouse model. Key features include hepatomegaly, lipid storage, elevated serum liver enzymes, and increased apoptosis.

This novel NPC1 antisense mouse model will allow delineation of the mechanism by which NPC1 dysfunction leads to liver cell death.