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

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

doi:10.1186/s12944-019-1088-2

Abstract

BackgroundNiemann-Pick disease type C1 (NPC1) is an autosomal-recessive lipid-storage disorder with an estimated minimal incidence of 1/120,000 live births. Besides other neuronal and visceral symptoms, NPC1 patients develop spleen dysfunction, isolated spleno- or hepatosplenomegaly and infections. The mechanisms of splenomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood.MethodsHere, we used an NPC1 mouse model to study a splenoprotective effect of a treatment with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone and showed that this treatment has a positive effect on spleen morphology and lipid metabolism.ResultsDisease progress can be halted and blocked at the molecular level. Mutant Npc1 (Npc1−/−) mice showed increased spleen weight and increased lipid accumulation that could be avoided by our treatment. Also, FACS analyses showed that the increased number of splenic myeloid cells in Npc1−/− mice was normalized by the treatment. Treated Npc1−/− mice showed decreased numbers of cytotoxic T cells and increased numbers of T helper cells.ConclusionsIn summary, the treatment promotes normal spleen morphology, stabilization of lipid homeostasis and blocking of inflammation, but alters the composition of T cell subtypes.

Highlights

Niemann-Pick disease type C1 (NPC1) is an autosomal-recessive lipid-storage disorder with an estimated minimal incidence of 1/120,000 live births
Earlier research had shown a notable change of the liverto–body weight ratio of Npc1−/− mice after therapy [30]
The evaluation of SW/BW ratio showed that sham-treated Npc1−/− (n = 9) (0.08868 ± 0.02956) mice had an increased SW/BW ratio compared to sham-treated Npc1+/+ (n = 11) (0.05866 ± 0.01769) mice (Fig. 1b, p = 0.250)

Summary

Introduction

Niemann-Pick disease type C1 (NPC1) is an autosomal-recessive lipid-storage disorder with an estimated minimal incidence of 1/120,000 live births. Besides other neuronal and visceral symptoms, NPC1 patients develop spleen dysfunction, isolated spleno- or hepatosplenomegaly and infections. Niemann-Pick Disease Type C1 (NPC1) is a rare, autosomal-recessive, lysosomal lipid storage disease with hepatosplenomegaly and progressive neurological involvement [1,2,3,4]. It has been shown that the altered NK cell frequency in Npc1−/− mice is similar to the decrease in NK cell frequency in the blood of NPC1 patients, with an important clinical relevance [20]. The involvement of NPC1 in sphingosine efflux of the lysosomes leads to reduced cellular S1P level in Npc1−/− mice and, alters these pathways [20, 24]

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Results

Conclusion