A therapy with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1

Neßlauer, Anna-Maria; Gläser, Anne; Gräler, Markus H.; Engelmann, Robby; Müller‐Hilke, Brigitte; Frank, Marcus; Burstein, Christine; Rolfs, Arndt; Neidhardt, John; Wree, Andreas; Witt, Martin; Bräuer, Anja U.

doi:10.1186/s12944-019-1088-2

Cited by 16 publications

(22 citation statements)

References 68 publications

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“…3), which correlates with increases in weights of these organs, particularly the spleen (Table 2). This finding parallels the observations of other studies of the NPC1 −/− mouse, which showed the spleen weight is increased in the untreated NPC1 −/− , relative to control mice, and that spleen weights are increased further by therapy 20 . Third, chronic THL administration produces visible reductions in the vacuolation of cells in the cerebral cortex (Fig.…”

Section: Discussionsupporting

confidence: 90%

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Jiang

Lee

Pardridge

2020

Sci Rep

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Niemann-Pick C1 (NPC1) is a lysosomal cholesterol storage disorder, that severely affects the brain, and is caused by mutations in the NPC1 gene, which encodes an intracellular membrane transporter of non-esterified cholesterol. Therapeutic options for NPC1 are few, and classical enzyme replacement therapy with the recombinant protein is not possible as the NPC1 gene product is an insoluble membrane protein, which increases the need for development of gene therapy for NPC1. While viral based gene therapy is under development, it is important to investigate alternative approaches to brain gene therapy without viral vectors. The present work develops a plasmid DNA approach to gene therapy of NPC1 using Trojan horse liposomes (THLs), wherein the plasmid DNA is encapsulated in 100 nm pegylated liposomes, which are targeted to organs with a monoclonal antibody against the mouse transferrin receptor. THLs were encapsulated with a 8.0 kb plasmid DNA encoding the 3.9 kb human NPC1 open reading frame, under the influence of a 1.5 kb platelet derived growth factor B (PDGFB) promoter. THLs were administered weekly beginning at 6-7 weeks in the NPC1 −/− null mouse, and delivery of the plasmid DNA, and NPC1 mRNA expression in brain, spleen, and liver were confirmed by quantitative PCR. THL treatment reduced tissue inclusion bodies in brain, and peripheral organs, but did not prolong lifespan in these mice. The work suggests that early treatment after birth may be required to reverse this disease model with NPC1 gene replacement therapy. Niemann-Pick C1 (NPC1) disease is an inherited lysosomal storage disorder caused by mutations in the gene encoding the NPC1 protein, which is a 200 kDa intracellular membrane transporter of non-esterified cholesterol. Cell cholesterol accumulation leads to intracellular inclusion bodies, which cause neurodegeneration, and hepatosplenomegaly 1. The diseases causes early mortality in most cases, and is associated with dementia, seizures, ataxia, and decreased audition 1. There is no approved therapy for NPC1. New treatments may be tested in the NPC1 null mouse (NPC1 −/−) such as the NPC1 m1N mouse 2,3 , and the systemic administration of large doses of hydroxypropyl beta cyclodextrin (HPβCD) to NPC1 −/− mice prolongs lifespan 4. HPβCD does not cross the blood-brain barrier (BBB) 5 , and HPβCD administration to NPC1 patients uses intrathecal administration via injections into the lumbar cerebrospinal fluid (CSF) 6. However, intrathecal drug delivery to brain only allows for drug exposure at the CSF surface of the brain 7 , and intrathecal HPβCD has not been approved. NPC1 gene therapy with adeno-associated virus (AAV) serotypes, e.g. AAV9, is possible, particularly with selfcomplementary AAV (scAAV), as these serotypes cross the BBB 8. However, the maximal size of the expression cassette that can be inserted in the scAAV is < 2.3 kb 9 , and the size of the NPC1 open reading frame alone is 3.9 kb. Single stranded AAV (ssAAV) traverses the BBB less efficiently 9,10 , but this viral genome will acce...

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Section: Discussionsupporting

confidence: 90%

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Jiang

Lee

Pardridge

2020

Sci Rep

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“…[3] The cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a well-established pharmaceutical excipient that has generated much interest as a potential treatment for NPC due to its high affinity for cholesterol and other NPC-relevant lipids. [18][19][20][21] The cyclodextrin (CD) drives a redistribution of the cholesterol from the LE/LY to the extracellular space but the mechanism behind it is not fully understood. In vitro, HPβCD has been shown to trigger the exocytosis of LE/LY content via a pathway that depends on the calcium channel MCOLN1, [22] and to promote lysosomal cholesterol exchange from the cellular plasma membrane to the serum lipoproteins, [23] suggesting a dual action inside and outside the cell.…”

Section: Introductionmentioning

confidence: 99%

Investigating 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

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Niemann‐Pick disease type C (NPC) is a severe disorder that is characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and sphingolipids. The compound 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half‐life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HPβCD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8–312 kDa) display a ninefold greater cholesterol complexation capacity than monomeric HPβCD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3 kDa HPβCD exhibits a longer half‐life than the monomeric HPβCD but it does not increase the life span of Npc1 mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging‐guided low intensity‐pulsed focused ultrasound (MRIg‐FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HPβCDs can elucidate CDs’ mechanism of action while the use of MRIg‐FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.

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“…It reduces the intracellular levels of hexosylceramide as well as of GM2 and GM3 gangliosides. Miglustat has been shown to delay neurological symptoms and prolong lifespans [7][8][9] in NPC animal models, suppress neurological deficits, such as gait disorder, dysphagia, cataplexy, and dystonia, and improve ambulation and swallowing abilities in patients with NPC [10][11][12][13][14]. Recently, Colaco et al [15] reported that miglustat appears to have a therapeutic potential against Tangier disease, a metabolic disease caused by a defect in ATP-binding cassette transporter 1, which can be misdiagnosed as NPC.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Hoque

Kondo

Sakata

et al. 2020

IJMS

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Niemann–Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.

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A therapy with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1

Cited by 16 publications

References 68 publications

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann‐Pick Disease Type C Using Crosslinked 2‐Hydroxypropyl‐β‐cyclodextrin

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

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