scholarly journals The potential of histone deacetylase inhibitors in Niemann - Pick type C disease

FEBS Journal ◽  
2013 ◽  
Vol 280 (24) ◽  
pp. 6367-6372 ◽  
Author(s):  
Michael Maceyka ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Type C ◽  
Niemann Pick

scholarly journals Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

2013 ◽  
Vol 10 (4) ◽  
pp. 688-697 ◽  
Author(s):  
Paul Helquist ◽  
Frederick R. Maxfield ◽  
Norbert L. Wiech ◽  
Olaf Wiest
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Type C ◽  
Niemann Pick

scholarly journals Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model

2021 ◽  
Author(s):  
◽  
Natalie Hammond
Keyword(s):  
Clinical Trial ◽  
Liver Disease ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Efficacy ◽  
Premature Death ◽  
Unesterified Cholesterol ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

<p>Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC disease.</p>

scholarly journals Normalization of Hepatic Homeostasis in theNpc1nmf164Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat

2016 ◽  
Vol 292 (11) ◽  
pp. 4395-4410 ◽  
Author(s):  
Andrew B. Munkacsi ◽  
Natalie Hammond ◽  
Remy T. Schneider ◽  
Dinindu S. Senanayake ◽  
Katsumi Higaki ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

scholarly journals Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells

2017 ◽  
Vol 58 (4) ◽  
pp. 695-708 ◽  
Author(s):  
Nina H. Pipalia ◽  
Kanagaraj Subramanian ◽  
Shu Mao ◽  
Harold Ralph ◽  
Darren M. Hutt ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Mutant Cells

scholarly journals Role of STARD4 and NPC1 in intracellular sterol transport

2016 ◽  
Vol 94 (6) ◽  
pp. 499-506 ◽  
Author(s):  
Frederick R. Maxfield ◽  
David B. Iaea ◽  
Nina H. Pipalia
Keyword(s):  
Mammalian Cells ◽  
Histone Deacetylase Inhibitors ◽  
Transport Pathways ◽  
Sterol Transport ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Type C ◽  
Niemann Pick ◽  
Lipid Storage Disorder

Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is tightly regulated. Cholesterol moves among membrane organelles by a combination of vesicular and nonvesicular transport pathways, but the details of these transport pathways are not well understood. In this review, we discuss the mechanisms for nonvesicular sterol transport with an emphasis on the role of STARD4, a small, soluble, cytoplasmic sterol transport protein. STARD4 can rapidly equilibrate sterol between membranes, especially membranes with anionic lipid headgroups. We also discuss the sterol transport in late endosomes and lysosomes, which is mediated by a soluble protein, NPC2, and a membrane protein, NPC1. Homozygous mutations in these proteins lead to a lysosomal lipid storage disorder, Niemann–Pick disease type C. Many of the disease-causing mutations in NPC1 are associated with degradation of the mutant NPC1 proteins in the endoplasmic reticulum. Several histone deacetylase inhibitors have been found to rescue the premature degradation of the mutant NPC1 proteins, and one of these is now in a small clinical trial.

scholarly journals An “Exacerbate-reverse” Strategy in Yeast Identifies Histone Deacetylase Inhibition as a Correction for Cholesterol and Sphingolipid Transport Defects in Human Niemann-Pick Type C Disease

2011 ◽  
Vol 286 (27) ◽  
pp. 23842-23851 ◽  
Author(s):  
Andrew B. Munkacsi ◽  
Fannie W. Chen ◽  
Matthew A. Brinkman ◽  
Katsumi Higaki ◽  
Giselle Domínguez Gutiérrez ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Synthetic Lethality ◽  
Model Organism ◽  
Histone Deacetylase Inhibition ◽  
A Genome ◽  
Lysosomal Accumulation ◽  
Type C ◽  
Niemann Pick ◽  
Lipid Storage Disorder ◽  
The Impact

Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1Δ strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1Δ strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This “exacerbate-reverse” approach can potentially be utilized in any model organism for any disease.

scholarly journals Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model

2021 ◽  
Author(s):  
◽  
Natalie Hammond
Keyword(s):  
Clinical Trial ◽  
Liver Disease ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Efficacy ◽  
Premature Death ◽  
Unesterified Cholesterol ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

<p>Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC disease.</p>

scholarly journals HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

2021 ◽  
Author(s):  
Nina H Pipalia ◽  
Syed Z Saad ◽  
Kangaraj Subramanian ◽  
Abigail Cross ◽  
Aisha Al-Motawa ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Cell Types ◽  
Hsp70 Expression ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Npc1 Gene ◽  
Abnormal Accumulation ◽  
Niemann Pick ◽  
Cholesterol Storage

Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in the clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see the correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.

scholarly journals Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells

2016 ◽  
Author(s):  
Nina H. Pipalia ◽  
Kanagaraj Subramanian ◽  
Shu Mao ◽  
William E. Balch ◽  
Frederick R. Maxfield
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Autosomal Recessive Disorder ◽  
Fibroblast Cell ◽  
Common Mutation ◽  
Cholesterol Accumulation ◽  
Late Endosomes ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Polytopic Membrane Protein

AbstractNiemann Pick C disease (NPC) is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. The most common mutation NPC1I1061T has been shown to cause endoplasmic reticulum associated degradation of the NPC1 protein. Treatment of patient derived NPC1I1061T fibroblasts with histone deacetylase inhibitors (HDACi) Vorinostat or Panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage. Herein we show that several other human NPC1 mutant fibroblast cell lines can also be corrected by Vorinostat or Panobinostat and that treatment with Vorinostat extends the lifetime of the NPC1I1061T protein. To test effects of HDACi on a large number of NPC1 mutants, we engineered a U2OS cell line to suppress NPC1 expression by shRNA and then transiently transfected these cells with 81 different NPC1 mutant constructs. The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 80% of the mutants showed reduced cholesterol accumulation when treated with Vorinostat or Panobinostat.

Sign in / Sign up

Export Citation Format

Share Document