Abstract
Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1-/-) and missense (Npc1nmf164 ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease.
Highlights
Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)approved therapy
We describe the impact of vorinostat in a murine model of NP-C disease caused by a missense mutation in the Npc1 gene. We show that this FDA-approved Histone deacetylase (HDAC) inhibitor normalizes hepatic transcriptional regulation of cholesterol, corrects apolipoprotein B homeostasis, and improves liver function and pathology, raising the possibility that this intervention may treat visceral NP-C disease
The Npc1nmf164 mouse model presents with a less severe form of the disease than the Npc1Ϫ/Ϫ murine model but exhibits an abbreviated life span, progressive weight loss, neurological impairment, and cellular lipid accumulation compared with control littermates [17]
Summary
NPC1 Missense Variants Can Be Refolded—In the Npc1nmf164 mouse, NP-C disease arises from a missense mutation at codon. Glycerol increased expression levels of the NPC1D1005G protein compared with untreated cells (Fig. 1) and in addition promoted its maturation to a higher molecular weight form. NPC1-deficient human osteosarcoma U2OS cells expressing the NPC1I1061T protein were treated with glycerol. To elucidate the possible contributions of lysosomal and proteasomal degradation to levels of the NPC1D1005G protein, the Npc1nmf164 fibroblasts were treated with 3-methyladenine (an autophagy inhibitor) and two inhibitors of the proteasome, MG132 and lactacystin. Each of these treatments increased expression and maturation of the NPC1D1005G protein (Fig. 1), implicating lysosomal and proteasomal pathways in the degradation of misfolded forms of the NPC1D1005G protein
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