Anti-Inflammatory Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Pathology in Niemann–Pick Type C Disease

Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features.

Download Full-text

Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.757482 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lien Van Hoecke ◽

Caroline Van Cauwenberghe ◽

Kristina Dominko ◽

Griet Van Imschoot ◽

Elien Van Wonterghem ◽

...

Keyword(s):

Choroid Plexus ◽

Premature Death ◽

Loss Of Function ◽

Lipid Storage Disease ◽

Niemann Pick Disease ◽

Progressive Neurodegeneration ◽

Type C ◽

Niemann Pick

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

Download Full-text

Abstract 19300: Drug Screening in Human Neutral Lipid Storage Disease iPSCells Identifies Modulators of Intracellular Lipid Metabolism That Reduce Disease Phenotype in vitro

Circulation ◽

10.1161/circ.130.suppl_2.19300 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Rajarajan Kuppusamy ◽

Becca Feistritzer ◽

Marc Engels ◽

Anthony Sturzu ◽

Karolina Plonowska ◽

...

Keyword(s):

Neutral Lipid ◽

Drug Screening ◽

Lipid Accumulation ◽

Storage Disease ◽

Lipid Storage ◽

Disease Phenotype ◽

Lipid Storage Disease ◽

Neutral Lipid Storage Disease ◽

Induced Pluripotent

Induced pluripotent stem cells (iPSCs) hold great promise as in vitro disease models for pathway discovery and therapeutic drug screening. Here, we generated an in vitro model of neutral lipid storage disease, myopathy subtype (NLSD-M), a condition characterized by a marked elevation of lipid accumulation in cardiac and skeletal muscle due to the loss of functional adipose triglyceride lipase (ATGL), by reprogramming patient fibroblasts into iPSCs. These hiPSCs were confirmed of carrying mutations in exon 5and exon 7 of the ATGL gene and were shown to recapitulate the disease phenotype by the presence of Oil Red O positive lipid granules in cardiomyocytes. To corroborate this finding, expression of metabolic genes such as Peroxisome proliferator-activated receptors (PPAR-a and PPAR-g) were significantly decreased in diseased cardiomyocytes compared to control. Furthermore, the down-regulation of PPAR-gamma coactivators (PGC-1a and PGC-1b) and PPAR target genes expression were associated with increased lipid accumulation in vitro. Utilizing the previously identified compounds that induces glycolysis and suppresses oxidative respiration, we found that the accumulation of intracellular lipids in cardiomyocytes was reduced in treated cells when compared with un-treated cells (0.041 ± 0.02 vs 0.186 ± 0.05). Strikingly, such a treatment effect was not observed when Wild Type iPSC derived cardiomyocytes was studied instead, suggesting a disease-specific effect of the identified drugs. Our results represent one of the first successful human induced Pluripotent Stem Cell validation of high throughput drug screening hits from murine iPSC lines. Given the increased prevalence of NLSD-Min the Japanese population, our findings raise the prospect that a treatment for this devastating disease using drug hits from in vitro iPSC screening may be feasible in the near future.

Download Full-text

Effects of curcumin nanoformulations on cellular function in Niemann-Pick disease type C astrocytes

10.1101/135830 ◽

2017 ◽

Cited By ~ 1

Author(s):

Emily Maguire ◽

Luke J. Haslett ◽

Joanne L. Welton ◽

Helen Waller-Evans ◽

Jule Goike ◽

...

Keyword(s):

Clinical Evidence ◽

Disease Type ◽

Lipid Storage ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

And Function ◽

Pick Disease

AbstractNiemann-Pick disease type C1 (NPC disease) is a neurodegenerative multi-lipid lysosomal storage disease caused by mutations in the NPC1 gene presenting with reduced lysosomal Ca2+ signalling and inhibited late endosome-lysosome transport. Elevating cytosolic Ca2+ levels in NPC cells has been shown to reduce lysosomal lipid storage. Treating Npc1-/- mice with the Ca2+ modulator curcumin led to reduced lipid storage, improved life expectancy and function. These studies led to reported utilisation of curcumin supplements by NPC disease families despite there being no clinical evidence of benefit and a report indicating no benefit of nanoformulated curcumin in Npc1-/- mice. The aim of this study was to determine whether various commercially available curcumin nanoformulations were capable of reproducing the findings obtained with unformulated pharmaceutical grade curcumin. We compared seven curcumin nanoformulations in Npc1-/- mouse astrocytes. All the nanoformulations elevate cytosolic Ca2+ levels but only two lowered lysosomal lipid storage. Importantly, some caused elevations in NPC lysosomal storage and/or decreased cellular viability. Although this is an in vitro study, our findings suggest that care should be taken when contemplating the use of curcumin supplements for NPC disease.

Download Full-text