Heat shock protein-based therapy for sphingolipidoses

Kirkegaard, Tove; Gray, James; Priestman, David A.; Wallom, Kerri‐Lee; Petersen, Nikolaj H.T.; Ingemann, Linda; Drndarski, Svetlana; Klein, Alexander; Jørgensen, Signe Humle; Atkins, Jennifer; Olsen, Ole Dines; Smith, David A.; Hinsby, Anders M.; Begley, David J.; Jäättelä, Marja; Platt, Frances M.

doi:10.1016/j.ymgme.2016.11.178

Cited by 3 publications

(4 citation statements)

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“…Several strategies to increase residual mutant NPC1, including histone deacetylase (HDAC) inhibitors and HSP70 analogues, are currently being explored for clinical use (21,36,37). In principle, these strategies are believed to be efficacious since most NP-C patients still express substantial amounts of mutant NPC1 protein with preserved cholesterol-transporting function (12,23).…”

Section: Discussionmentioning

confidence: 99%

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

et al. 2016

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Niemann-Pick type C disease (NP-C) is a progressive lysosomal lipid storage disease caused by mutations in the NPC1 and NPC2 genes. NPC1 is essential for transporting cholesterol and other lipids out of lysosomes, but little is known about the mechanisms that control its cellular abundance and localization. Here we show that a reduction of TMEM97, a cholesterol-responsive NPC1-binding protein, increases NPC1 levels in cells through a post-transcriptional mechanism. Reducing TMEM97 through RNA-interference reduces lysosomal lipid storage and restores cholesterol trafficking to the endoplasmic reticulum in cell models of NP-C. In TMEM97 knockdown cells, NPC1 levels can be reinstated with wild type TMEM97, but not TMEM97 missing an ER-retention signal suggesting that TMEM97 contributes to controlling the availability of NPC1 to the cell. Importantly, knockdown of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol storage in an NPC1-dependent manner. Our findings propose TMEM97 inhibition as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target for NP-C.

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Section: Discussionmentioning

confidence: 99%

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

et al. 2016

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“…Further studies showed that administration of the drug completely restored Hsp70 levels in the brain, but provided only a small increase in Hsp70 in the liver. The studies of Kikeegard et al confirmed the neuroprotective effect of arimoclomol treatment in Npc1 −/− mice (Kirkegaard et al 2017).…”

Section: Arimoclomolmentioning

confidence: 85%

“…Arimoclomol is currently undergoing clinical trials to assess efficacy in the treatment of various neurodegenerative diseases (Kieran et al 2004;Cudkowicz et al 2008;Lanka et al 2009;Parfitt et al 2014;Kalmar et al 2014;Benatar et al 2009). Due to recent reports on the main role of HSP70 in the maturation of the NPC1 protein (Nakasone et al 2014), as well as the positive effects of upregulation of heat shock proteins in vitro in NPC and other lysosomal diseases (Mu et al 2008;Yang et al 2014;Zampieri et al 2012;Macías-Vidal et al 2014), this therapy has become a promising research topic (Mengel et al 2020) Kirkegaard et al 2017 undertook in vitro testing of arimoclomol in primary fibroblasts from NPC patients and in vivo in the Npc1 −/− mouse model.…”

Section: Arimoclomolmentioning

confidence: 99%

Treatment trials in Niemann-Pick type C disease

2021

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Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood–brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

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“…Several potential therapeutic drugs have been studied in NPC disease, including miglustat, a glycosphingolipid synthesis inhibitor; 82 histone deacetylase inhibitors (e.g. vorinostat), which regulates gene expression; 83 cyclodextrins which are cyclic oligosaccharide that complex with cholesterol; 84 arimoclomol that acts as a co-inducer of heat shock proteins (HSPs); 85 and N-acetyl-L-leucine (NALL), which is a modified and acetylated derivative of a natural essential amino acid (leucine). 86 2.2.1 Miglustat.…”

Section: Proteome Response To Drug Treatmentmentioning

confidence: 99%