Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease

Vincent M, Sayre NL, Graham MJ, Crooke RM, Shealy DJ, Liscum L. Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease. PLoS One. 2010 Sep 23;5(9):e12941. doi: 10.1371/journal.pone.0012941. PMID: 20886067; PMCID: PMC2944848.


Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF) α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048) will slow the progression of NPC liver disease.

Methodology/principal findings: Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown.

Conclusions/significance: Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

Conflict of interest statement
Competing Interests: MJG and RMC are employees of Isis Pharmaceuticals. DJS is an employee of Centocor Research and Development, a subsidiary of Johnson & Johnson which markets anti-TNF biologics Remicade and Simponi. All other authors have declared that no competing interests exist. All authors agree to make freely available the materials and information described in this publication that are reasonably requested by others for the purpose of academic, non-commercial research. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.