scholarly journals In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

2019 ◽  
Vol 20 (5) ◽  
pp. 1152 ◽  
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Madoka Fukaura ◽  
Yusei Yamada ◽  
Shuichi Nakahara ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Disease Type ◽  
Cholesterol Trafficking ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Deficient Mice ◽  
Pick Disease

Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.

scholarly journals Effect of Maltosyl-Beta-cyclodextrin on in vitro and in vivo models of Niemann-Pick disease type C

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-8-13
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Yusei Yamada ◽  
Madoka Fukaura ◽  
Shuichi Nakahara ◽  
...  
Keyword(s):  
Disease Type ◽  
In Vivo Models ◽  
Beta Cyclodextrin ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

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

2020 ◽  
Author(s):  
Dario Carradori ◽  
Hsintsung Chen ◽  
Beat Werner ◽  
Aagam Shah ◽  
Chiara Leonardi ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
High Doses ◽  
Niemann Pick ◽  
Stable Forms ◽  
Pick Disease

AbstractNiemann-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.

scholarly journals Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Seung-Eun Lee ◽  
Nari Shin ◽  
Myung Geun Kook ◽  
Dasom Kong ◽  
Nam Gyo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lysosomal Storage Disorder ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Storage Disorder ◽  
Niemann Pick ◽  
Pick Disease

AbstractRecent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.

In vivo quantification of brain injury in adult Niemann–Pick Disease Type C

2011 ◽  
Vol 103 (2) ◽  
pp. 138-141 ◽  
Author(s):  
Wafaa Zaaraoui ◽  
Lydie Crespy ◽  
Audrey Rico ◽  
Anthony Faivre ◽  
Elisabeth Soulier ◽  
...  
Keyword(s):  
Brain Injury ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

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

2017 ◽  
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.

Graphene Quantum Dots Alleviate Impaired Functions in Niemann-Pick Disease Type C in Vivo

Nano Letters ◽  
2021 ◽  
Author(s):  
Insung Kang ◽  
Je Min Yoo ◽  
Donghoon Kim ◽  
Juhee Kim ◽  
Myung Keun Cho ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Graphene Quantum Dots ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

ANALYSIS OF CHOLESTEROL AND OXYSTEROL LEVELS IN NIEMANN PICK DISEASE TYPE C MICE AND PATIENTS

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
S Tay ◽  
X He ◽  
AM Jenner ◽  
BS Wong ◽  
WY Ong
Keyword(s):  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease
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