betadex and miglustat

Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Animals; Apoptosis; beta-Cyclodextrins; Cell Proliferation; Disease Models, Animal; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Olfactory Mucosa; Pregnanolone; Proteins

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Animals; B-Lymphocytes; beta-Cyclodextrins; Biomarkers; Bone Marrow Transplantation; Case-Control Studies; Child; Child, Preschool; Humans; Infant; Intracellular Signaling Peptides and Proteins; Lysosomes; Mice; Mice, Inbred BALB C; Mice, Knockout; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Prospective Studies; Proteins; Severity of Illness Index; Treatment Outcome

Niemann-Pick type C (NPC)1 is a rare neurodegenerative disease for which treatment options are limited. A major barrier to development of effective treatments has been the lack of validated biomarkers to monitor disease progression or serve as outcome measures in clinical trials. Using targeted metabolomics to exploit the complex lipid storage phenotype that is the hallmark of NPC1 disease, we broadly surveyed Npc1(-/-) mouse tissues and identified elevated species across multiple sphingolipid classes that increased with disease progression. There was a striking accumulation of sphingoid bases, monohexosylceramides (MCs), and GM2 gangliosides in liver, and sphingoid bases and GM2 and GM3 gangliosides in brain. These lipids were modestly decreased following miglustat treatment, but markedly decreased in response to treatment with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), two drugs that have shown efficacy in NPC1 animal models. Extending these studies to human subjects led to identification of sphingolipid classes that were significantly altered in the plasma of NPC1 patients. Plasma MCs and ceramides were elevated, whereas sphingoid bases were reduced in NPC1 subjects. Intervention with miglustat in NPC1 patients was accompanied by striking alterations in plasma (reductions in GM1 and GM3 gangliosides) and cerebrospinal fluid (CSF) (increased MCs) sphingolipids. Similar alterations were observed in the CSF from the NPC1 feline model following HP-β-CD treatment. Our findings suggest that these lipid biomarkers may prove useful as outcome measures for monitoring efficacy of therapy in clinical trials.

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Biomarkers; Cats; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; Female; Gangliosides; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Niemann-Pick Disease, Type C; Organ Specificity; Sphingolipids; Sulfoglycosphingolipids; Tandem Mass Spectrometry

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Animals; beta-Cyclodextrins; Child; Disease Models, Animal; Diseases in Twins; Drugs, Investigational; Histone Deacetylases; Humans; Infusions, Intravenous; Injections, Spinal; Mice; Niemann-Pick Disease, Type C; Research; United States; United States Food and Drug Administration

Galectins are potent effectors with conspicuous cell-type-specific activity profile. Its occurrence poses the question on the nature of the underlying biochemical determinants, in human SK-N-MC neuroblastoma cells involved in negative growth regulation. Since increase of surface presentation of ganglioside GM1 and homodimeric galectin-1 precedes growth inhibition, a direct interaction is suggested. We thus examined cell binding depending on glucosylceramide synthesis. It was drastically reduced by N-butyldeoxynojirimycin and threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adding decisive evidence for the assumed galectin/ganglioside binding. Glycoproteins do not compensate ganglioside depletion which was verified by measuring lipid-bound sialic acid. Binding affinity is significantly lowered by disrupting microdomain integrity, also effective for the competitive inhibitor galectin-3. This was caused by cell treatment with either 2-hydroxypropyl-beta-cyclodextrin or filipin III. In this cell system, target specificity and topology of ligand presentation act together to enable high-affinity binding.

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Anti-Bacterial Agents; beta-Cyclodextrins; Cell Adhesion; Cell Membrane; Enzyme Inhibitors; Excipients; Filipin; G(M1) Ganglioside; Galectin 1; Galectin 3; Glycoside Hydrolase Inhibitors; Humans; Membrane Microdomains; Morpholines; Neuroblastoma; Tumor Cells, Cultured

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.. Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.. Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

Topics: 1-Deoxynojirimycin; 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Cholesterol; Cyclodextrins; Disease Models, Animal; Disease Progression; Drug Synergism; Enzyme Inhibitors; Glycosphingolipids; Mice; Mice, Transgenic; Neurons; Niemann-Pick Disease, Type C; Pregnanolone; Treatment Outcome