The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease

Hammond, Natalie; Munkacsi, Andrew B.; Sturley, Stephen L.

doi:10.1016/j.bbalip.2019.04.002

Cited by 50 publications

(56 citation statements)

References 172 publications

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“…Npc1 -/microglia offer potential for therapeutic intervention and biomarker studies, but translation of animal models to human patients is limited due to the very small number of NPC patients (estimated at 1:100 000 live births) and limited access to viable human brain tissue (Hammond, Munkacsi et al, 2019). As a compromise, we explored human peripheral macrophages for their phenotypic alterations in NPC.…”

Section: Macrophages From Npc Patients Feature Murine Npc1 -/Microglimentioning

confidence: 99%

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1 -/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1 -/microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1 -/microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1 -/microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

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Section: Macrophages From Npc Patients Feature Murine Npc1 -/Microglimentioning

confidence: 99%

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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“…This could be partially overcome with MRIg-FUS, with which promising results were obtained promoting the penetration of high molecular weight CDs in the brain parenchyma. In view of the technology's increasing availability in hospitals worldwide, MRIg-FUS should be further investigated for its potential implementation in NPC patients receiving CDs or other treatments [44]. In view of previously published work, these data further suggest that sustained release formulations of CDs, for instance in the form of a biodegradable CD-based implant, could potentially simplify the dosing regimen while potentially improving the treatment efficacy.…”

Section: Discussionmentioning

confidence: 92%

“…NPC is a devastating neurovisceral disorder with a profound impact on the patient's life, imposing tremendous limitations in basic physiological and social needs. The progression of the disease leads NPC patients to inexorably lose their autonomy, while financial costs, emotional stress, and logistical complexities increase [1][2][3][4][5][6][7] [44]. HPβCD is one of the most studied molecules for NPC treatment and is being tested in several clinical trials, six of them are currently active (source: clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

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Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

Carradori

Chen

Werner

et al. 2020

Preprint

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Niemann-Pick Disease Type C (NPC) is a severe neurovisceral disorder that is pathophysiologically characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and multiple sphingolipids, including sphingosine. The compound 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a compound with high cholesterol complexation capacity and is currently under clinical investigation for the treatment of NPC. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. It has been reported in mice that HPβCD’s circulation time and efficacy can be improved by increasing its size via polymerization, but the biodegradable nature of these systems did not allow the contribution of the macromolecule to the activity to be determined. In this work, stable forms of polymerized HPβCD were generated (via epichlorohydrin crosslinking) to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) displayed a 10-fold greater complexation capacity towards cholesterol than monomeric HPβCD but were taken up by cells to a lower extent (in a size-dependent fashion), resulting in an overall comparable in vitro effect on intracellular cholesterol accumulation that was dependent on cholesterol complexation. When tested in vivo, the crosslinked 19.3 kDa HPβCD exhibited a longer terminal half-life than the monomeric HPβCD. However, it did not increase the life span of Npc1 mice, possibly due to reduced organ penetration and brain diffusion consequence of its large molecular weight. This could be circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increased the brain penetration of the CD. In conclusion, stable forms of polymerized HPβCD constitute valuable tools to elucidate CDs’ mechanism of action. Moreover, the use of MRIg-FUS to maximize CDs tissue penetration warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the treatment of NPC.Graphical abstractThe 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a well-established pharmaceutical excipient that can complex cholesterol and is currently under clinical investigation to treat Niemann-Pick Disease Type C (NPC). However, high doses of the drug are needed to achieve a therapeutic effect. Using stable and long circulating crosslinked HPβCDs, this study attempts to further understand the mechanisms behind CDs’ activity.

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“…The ndings demonstrate that cholesterol esteri cation is signi cantly decreased in the PBMCs of individuals with NPC compared with healthy individuals (p < 0.0001). Mutations in the NPC genes either result in reduced protein function because of limited binding capacity, or reduced abundance because of a more rapid degradation of the dysfunctional protein [2,4,54,55]; therefore, NPC function is not expected to change with disease progression. Accordingly, no signi cant change in cholesterol esteri cation was observed during the study, nor did cholesterol esteri cation correlate with disease progression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study 

Mengel¹,

Bembi²,

Toro

et al. 2020

Preprint

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BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937). ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

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The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease

Cited by 50 publications

References 172 publications

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study

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The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease

Cited by 50 publications

References 172 publications

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study&nbsp;

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Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study