ABSTRACT
Niemann-Pick disease (NPD) type A and type B are part of the spectrum disease of the acid sphingomyelinase deficiency (ASMD). Plasma lipid abnormalities are frequently associated with both NPD-A and NPD-B, and include decreased high-density lipoprotein cholesterol (HDL-C), increased low-density lipoprotein cholesterol (LDL-C), and hypertriglyceridemia. The atherogenic lipid profile has been associated to early atherosclerotic vascular disease and coronary artery disease in NPD-B patients. Thus, early treatment of dyslipidemia in these patients is advisable. We present here a pediatric case of NPD-B with an atherogenic lipid profile not responding to lifestyle changes, low fat diet, and daily supplementation with plant sterols. We reviewed the existing literature about the treatment strategies for dyslipidemia in ASMD patients, with a special focus on the pediatric age. Finally, we speculated on the mechanisms underlying dyslipidemia in this disorder. The clinical experiences in lipid-lowering strategies in NPD-B patients are limited, in particular in the pediatric age. Olipudase alfa appears as the most promising candidate for improving lipid profile. Since olipudase alfa is not yet approved and, due to its costs, it will probably not be available for all patients worldwide, further research is needed to broaden our knowledge on this clinical need and to evaluate the efficacy and the long-term effects of lipid-lowering agents in ASMD patients. A deep understanding of the pathophysiology of dyslipidemia in ASMD may promote the identification of new targets and support the identification of new therapeutic strategies.
Subject(s)
Atherosclerosis , Niemann-Pick Disease, Type A , Niemann-Pick Disease, Type B , Niemann-Pick Diseases , Atherosclerosis/drug therapy , Child , Cholesterol, LDL , Humans , Niemann-Pick Disease, Type A/drug therapy , Niemann-Pick Disease, Type B/drug therapy , Niemann-Pick Diseases/chemically induced , Niemann-Pick Diseases/drug therapy , Sphingomyelin Phosphodiesterase/therapeutic useSubject(s)
Drug Approval , Dystrophin/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Hydroxylamines/therapeutic use , Lymphoma, B-Cell, Marginal Zone/drug therapy , Muscular Dystrophy, Duchenne/drug therapy , Niemann-Pick Diseases/drug therapy , Humans , United States , United States Food and Drug AdministrationABSTRACT
Lysosomial diseases and autoimmune diseases are systemic disorders. Their clinical manifestations can overlap with the broad spectrum of one another. Their association has been rarely reported. We report a new case of systemic lupus erythematous (SLE) associated to antiphospholipid syndrome (APS) and Hashimoto thyroiditis occurring in Niemann-Pick disease (NPD) type B patient. A 42-year-old woman with a familial history of NPD was diagnosed with a NPD type B at the age of ten. Twenty years later (2008), she complained of inflammatory arthralgia with acute dyspnea. She was diagnosed with SLE (according to ACR criteria) and Hashimoto disease with positive IgG anti-cardiolipin and IgA anti-beta2 glycoprotein. In 2018, she presented a left segmental pulmonary embolism. Antiphospholipid syndrome was retained. She was treated with steroids, hydroxychloroquine, anticoagulation therapy and levothyroxine. Her SLE treatment was re-enforced by cyclophosphamide because of corticosteroid dependence and recurrent hemolytic crises.
Subject(s)
Antiphospholipid Syndrome/diagnosis , Hashimoto Disease/diagnosis , Lupus Erythematosus, Systemic/diagnosis , Niemann-Pick Diseases/diagnosis , Adult , Antiphospholipid Syndrome/drug therapy , Dyspnea/etiology , Female , Hashimoto Disease/drug therapy , Humans , Lupus Erythematosus, Systemic/drug therapy , Niemann-Pick Diseases/drug therapy , Pulmonary Embolism/diagnosis , Tomography, X-Ray ComputedABSTRACT
Recently, the application of ß-cyclodextrins (ß-CDs) as therapeutic agents has received considerable attention. ß-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of ß-CDs, the use of ß-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of ß-CDs for NPC disease. PRXs are supramolecular polymers composed of many CDs threaded onto a linear polymer chain and capped with bulky stopper molecules. In this review, the design of PRXs and their therapeutic applications are described. To achieve the intracellular release of threaded ß-CDs from PRXs, stimuli-cleavable linkers are introduced in an axle polymer of PRXs. The stimuli-labile PRXs can dissociate into their constituent molecules by a cleavage reaction under specific stimuli, such as pH reduction in lysosomes. The release of the threaded ß-CDs from acid-labile PRXs in acidic lysosomes leads to the formation of an inclusion complex with the cholesterol that has accumulated in NPC disease patient-derived fibroblasts, thus promoting the extracellular excretion of the excess cholesterol. Moreover, the administration of PRXs to a mouse model of NPC disease caused significant suppression of the tissue accumulation of cholesterol, resulting in a prolonged life span in the model mice. Additionally, the induction of autophagy by the methylated ß-CD-threaded PRXs (Me-PRXs) is described. Accordingly, the stimuli-labile PRXs are expected to be effective carriers of CDs for therapeutic applications.
Subject(s)
Cyclodextrins , Drug Carriers , Poloxamer , Rotaxanes , beta-Cyclodextrins/administration & dosage , Animals , Autophagy/drug effects , Cholesterol/metabolism , Cyclodextrins/chemistry , Cyclodextrins/metabolism , Disease Models, Animal , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Design , Fibroblasts/metabolism , Humans , Hydrogen-Ion Concentration , Lysosomes/metabolism , Macromolecular Substances , Methylation , Mice , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/metabolism , Poloxamer/chemistry , Poloxamer/metabolism , Rotaxanes/chemistry , Rotaxanes/metabolism , beta-Cyclodextrins/metabolism , beta-Cyclodextrins/pharmacologySubject(s)
Humans , Female , Middle Aged , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/surgery , Sphingomyelin Phosphodiesterase/therapeutic use , Niemann-Pick Disease, Type A/drug therapy , Anesthesia , Anesthesia, General/instrumentation , Anesthesia, General/methods , Anesthesia, General , Cholesterol/analysis , Anesthesia, Inhalation/methods , Anesthesia, Inhalation , Neuromuscular Agents/therapeutic use , Neuromuscular Blocking Agents/therapeutic useABSTRACT
Niemann-Pick disease (NPD) is a group of distinct rare disorders (i.e. NPD-A; NPD-B; NPD-C) - with autosomal recessive inheritance pattern - within the class of the inborn disorders of the sphingolipid metabolism (called sphingolipidoses). Since patients with NPD-A do not survive into adulthood and most patients with NPD-B are free from neuropsychiatric symptoms we discuss only briefly type-A and -B NPD and mainly constrict our review discussing the neuropsychiatric symptoms along with the pathomechanism and the treatment of NPD-C. NPD-C is clinically heterogeneous, with notable variations in age at onset, course and symptoms. Along with systemic signs, neurologic and psychiatric symptoms are quite frequent in NPD-C and in its adult form sometimes psychiatric symptoms are the first ones appearing. Unfortunately, the majority of clinicans (including adult psychiatrists and neurologists) are not aware of the symptom group characteristic to NPD-C so patients with this disorder are frequently misdiagnosed in the clinical practice. Since neuropsychiatric manifestations of NPD-C may be treated with a substrate reduction agent (miglustat) with greater awareness of the identification of neuropsychiatric symptoms in due course is the prerequisite of proper and early diagnosis and treatment.
Subject(s)
Niemann-Pick Diseases/diagnosis , Niemann-Pick Diseases/psychology , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/therapeutic use , Age of Onset , Cataplexy/etiology , Cognition Disorders/etiology , Enzyme Inhibitors/therapeutic use , Humans , Niemann-Pick Disease, Type A/diagnosis , Niemann-Pick Disease, Type A/psychology , Niemann-Pick Disease, Type B/diagnosis , Niemann-Pick Disease, Type B/psychology , Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/psychology , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/enzymology , Niemann-Pick Diseases/genetics , Sphingolipids/metabolism , Sphingomyelin Phosphodiesterase/deficiency , Sphingomyelin Phosphodiesterase/metabolismSubject(s)
Humans , Female , Child, Preschool , Cyclodextrins/therapeutic use , Niemann-Pick Diseases/drug therapyABSTRACT
High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin-cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann-Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future.
Subject(s)
Cardiovascular Diseases/metabolism , Lipid Metabolism , Lipoproteins, HDL/metabolism , Niemann-Pick Diseases/metabolism , Sphingomyelins/metabolism , Animals , Biological Transport, Active , Cardiovascular Diseases/diet therapy , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/pathology , Humans , Lipoproteins, HDL/chemistry , Niemann-Pick Diseases/diet therapy , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/pathology , Sphingomyelins/chemistry , Structure-Activity RelationshipABSTRACT
Niemann-Pick type C disease is an inherited autosomal recessive neurodegenerative disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-ß-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113 ± 0.010 ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039 ± 0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilisation and clearance of cholesterol from the CNS.
Subject(s)
Blood-Brain Barrier/metabolism , Cholesterol/metabolism , Neurons/drug effects , Neurons/metabolism , Niemann-Pick Diseases/drug therapy , beta-Cyclodextrins/therapeutic use , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Blood-Brain Barrier/drug effects , Capillary Permeability/drug effects , Drug Evaluation, Preclinical , Injections, Intraperitoneal , Intracellular Signaling Peptides and Proteins , Mice , Mice, Inbred BALB C , Mice, Knockout , Neurons/pathology , Niemann-Pick C1 Protein , Niemann-Pick Diseases/genetics , Niemann-Pick Diseases/metabolism , Niemann-Pick Diseases/pathology , Perfusion , Proteins/genetics , Proteins/metabolism , beta-Cyclodextrins/administration & dosageABSTRACT
PURPOSE OF REVIEW: This review summarizes the recent findings on the mechanism of action of the Niemann-Pick type C (NPC) proteins and their bypass by cyclodextrin. RECENT FINDINGS: NPC disease is caused by dysfunction in either the NPC1 or NPC2 protein. These proteins function in the same pathway for the removal of unesterified cholesterol from late endosomes/lysosomes. In NPC-deficient cells, cholesterol derived from the endocytosis of LDLs becomes sequestered in the late endosomes/lysosomes. Recent studies have indicated that these two cholesterol-binding proteins act in tandem in mediating the egress of cholesterol from the late endosomes/lysosomes. Patches of amino acids on NPC1 and NPC2 appear to interact so that the hydrophobic transfer of cholesterol from NPC2 to NPC1 is achieved. Although no effective treatment for NPC disease is currently available, exciting new studies have shown that treatment of NPC-deficient mice with the cholesterol-binding compound, cyclodextrin, reduces the neurodegeneration and markedly extends the life span of Npc1-/- mice, suggesting a potential therapeutic approach for the treatment of individuals with NPC disease. SUMMARY: Experimental data are consistent with a model for the sequential action of the NPC1 and NPC2 proteins in moving cholesterol out of the late endosomes/lysosomes. Recent data demonstrate that treatment of NPC-deficient mice with cyclodextrin extends their life span, thereby suggesting a potential therapy for NPC patients.
Subject(s)
Carrier Proteins/metabolism , Glycoproteins/metabolism , Lipid Regulating Agents/pharmacology , Membrane Glycoproteins/metabolism , beta-Cyclodextrins/pharmacology , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Brain/metabolism , Brain/physiopathology , Carrier Proteins/genetics , Cholesterol/metabolism , Endosomes/metabolism , Glycoproteins/genetics , Humans , Intracellular Signaling Peptides and Proteins , Lysosomes/metabolism , Membrane Glycoproteins/genetics , Mutation , Niemann-Pick C1 Protein , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/genetics , Vesicular Transport ProteinsABSTRACT
OBJECTIVE: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-ß (Aß) plaques. Lipids affect γ-secretase-dependent amyloid precursor protein (APP) metabolism that generates Aß in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans. METHODS: We examined Aß in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for Aß(38), Aß(40), Aß(42), α-cleaved soluble APP, ß-cleaved soluble APP, total-tau, and phospho-tau. RESULTS: Aß release was markedly increased in NPC, with a shift toward the Aß(42) isoform. Levels of α- and ß-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower Aß(42) and total-tau than untreated patients. CONCLUSION: Increased CSF levels of Aß(38), Aß(40), and Aß(42) and unaltered levels of ß-cleaved soluble APP are consistent with increased γ-secretase-dependent Aß release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates γ-secretase-dependent Aß production in humans and may be of relevance to AD pathogenesis.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Niemann-Pick Diseases/enzymology , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/therapeutic use , Adolescent , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Protein Precursor/cerebrospinal fluid , Apolipoproteins E/genetics , Axons/pathology , Biomarkers/cerebrospinal fluid , Child , Child, Preschool , Cross-Sectional Studies , Female , Genotype , Glucosyltransferases/antagonists & inhibitors , Humans , Infant , Male , Niemann-Pick Diseases/cerebrospinal fluid , Niemann-Pick Diseases/drug therapy , Peptide Fragments/cerebrospinal fluid , Phosphoproteins/cerebrospinal fluid , Young Adult , tau Proteins/cerebrospinal fluidABSTRACT
The intestines have been proposed as the 'new player' in the field of atherosclerosis as a result of recent discoveries on intestinal cholesterol absorption and excretion. 'Niemann-Pick C1-like 1' is one of the most important transport proteins in the process of intestinal and biliary cholesterol absorption. Cholesterol is not only excreted via the hepato-biliary route but is also excreted directly into the intestinal lumen; this transintestinal cholesterol excretion is particularly important in mice. Other cholesterol transporters have also been identified, including the ABC transporters, which have been linked to rare disorders such as sitosterolemia. Inhibition of intestinal cholesterol absorption increases the hepatic synthesis of cholesterol and vis versa; several different genes and hormones play an important role in this process. When the effect of statins is insufficient or they cause too many side-effects, additional inhibition of intestinal cholesterol absorption is indicated.
Subject(s)
Anticholesteremic Agents/therapeutic use , Cholesterol/metabolism , Hypercholesterolemia/drug therapy , Hypercholesterolemia/metabolism , Intestinal Absorption/physiology , Humans , Intestinal Absorption/drug effects , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Membrane Transport Proteins , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/metabolismABSTRACT
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.
Subject(s)
Carbamates/chemical synthesis , Lipase/antagonists & inhibitors , Lysosomes/enzymology , Thiadiazoles/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Cell Line , Enzyme Reactivators/chemical synthesis , Enzyme Reactivators/chemistry , Enzyme Reactivators/pharmacology , Humans , Kinetics , Morpholines/chemical synthesis , Morpholines/chemistry , Morpholines/pharmacology , Niemann-Pick Diseases/drug therapy , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
The potent cholesterol absorption inhibitor ezetimibe was developed as a first-in-class drug for treating hypercholesterolemia even before its molecular target, Niemann-Pick C1-like 1 (NPC1L1), had been identified. The NPC1L1 protein mediates sterol transport across the enterocyte brush border membrane and is essential for intestinal cholesterol absorption, a major pathway controlling whole-body cholesterol homeostasis. An elucidation of the mechanism underlying NPC1L1-dependent cholesterol absorption would greatly facilitate the discovery and development of new cholesterol-lowering agents for treating hypercholesterolemia and other cholesterol-related metabolic disorders.
Subject(s)
Drug Delivery Systems/methods , Drug Discovery/methods , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Amino Acid Sequence , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Ezetimibe , Humans , Membrane Transport Proteins/metabolism , Molecular Sequence Data , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/metabolism , Technology, Pharmaceutical/methodsABSTRACT
Patients with Niemann-Pick disease (NPD) Types A and B have an inherited deficiency of acid sphingomyelinase (ASM) activity. The clinical spectrum of this disorder ranges from the infantile neurological form that results in death by 3 years of age (NPD Type A) to the non-neurological form that is compatible with survival into adulthood (NPD Type B). Intermediate cases have also been reported, and the disease is best thought of as a single entity with a spectrum of phenotypes. ASM deficiency is panethnic, but appears to be more frequent in individuals of Middle Eastern and North African descent. Current estimates of the disease incidence range from 0.5 to 1 per 100,000 births, although these approximations are thought to underestimate the true frequency of the disorder. The gene encoding ASM--SMPD1--has been studied extensively, and over 100 mutations in SMPD1 have been found to cause ASM-deficient NPD. Based on these findings, DNA-based carrier screening has been implemented in the Ashkenazi Jewish community. ASM-knockout mouse models also have been generated and used to investigate disease pathogenesis and treatment with stem cell transplantation, gene therapy and enzyme replacement therapy (ERT). Based on these studies, clinical trials of ERT are underway in patients with non-neurological ASM-deficient NPD.
Subject(s)
Niemann-Pick Diseases/etiology , Niemann-Pick Diseases/therapy , Sphingomyelin Phosphodiesterase/deficiency , Animals , Enzyme Inhibitors/therapeutic use , Enzyme Replacement Therapy , Genetic Therapy , Humans , Mice , Mice, Knockout , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/genetics , Sphingomyelin Phosphodiesterase/geneticsABSTRACT
Systemic administration of recombinant acid sphingomyelinase (rhASM) into ASM deficient mice (ASMKO) results in hydrolysis of the abnormal storage of sphingomyelin in lysosomes of the liver, spleen and lung. However, the efficiency with which the substrate is cleared from the lung, particularly the alveolar macrophages, appears to be lower than from the other visceral tissues. To determine if delivery of rhASM into the air spaces of the lung could enhance clearance of pulmonary sphingomyelin, enzyme was administered to ASMKO mice by intranasal instillation. Treatment resulted in a significant and dose-dependent reduction in sphingomyelin levels in the lung. Concomitant with this reduction in substrate levels was a decrease in the amounts of the pro-inflammatory cytokine, MIP-1alpha, in the bronchoalveolar lavage fluids and an improvement in lung pathology. Maximal reduction of lung sphingomyelin levels was observed at 7 days post-treatment. However, reaccumulation of the substrate was noted starting at day 14 suggesting that repeated treatments will be necessary to effect a sustained reduction in sphingomyelin levels. In addition to reducing the storage abnormality in the lung, intranasal delivery of rhASM also resulted in clearance of the substrate from the liver and spleen. Hence, pulmonary administration of rhASM may represent an alternative route of delivery to address the visceral pathology associated with ASM deficiency.
Subject(s)
Lung/metabolism , Lysosomes/metabolism , Niemann-Pick Diseases/drug therapy , Recombinant Proteins/therapeutic use , Sphingomyelin Phosphodiesterase/administration & dosage , Sphingomyelin Phosphodiesterase/therapeutic use , Sphingomyelins/metabolism , Administration, Intranasal , Animals , Bronchoalveolar Lavage Fluid/cytology , Disease Models, Animal , Female , Humans , Kinetics , Liver/metabolism , Liver/pathology , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Niemann-Pick Diseases/enzymology , Niemann-Pick Diseases/metabolism , Niemann-Pick Diseases/pathology , Recombinant Proteins/administration & dosage , Sphingomyelin Phosphodiesterase/genetics , Spleen/metabolism , Spleen/pathologyABSTRACT
Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene. These studies evaluated the effect of genetic background, deletion of additional genes, and administration of several agents on the age at death in a murine model of this disorder. Such factors as differing strain background or genetic drift within a given background in the npc1(-/-) mouse significantly altered the age at death and the degree of organ disease. Genetic deletion of Siat9 (GM3 synthetase) or Nr1h2 [liver X receptor (LXR)beta] shortened the life of the npc1(-/-) animals. Daily treatment of the npc1(-/-) mice with an LXR agonist or administration of a single dose of cyclodextrin, with or without the neurosteroid allopregnanolone, significantly slowed neurodegeneration and increased the lifespan of these animals. These data illustrate that the age at death of the npc1(-/-) mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrbeta), and administration of agents such as LXR agonists and, particularly, cyclodextrin. It is currently not clear which of these effects is nonspecific or which might relate directly to the molecular defect present in the NPC1 syndrome.
Subject(s)
DNA-Binding Proteins/genetics , Genetic Variation , Longevity , Proteins/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Sialyltransferases/genetics , Animals , Cyclodextrins/administration & dosage , DNA-Binding Proteins/agonists , Gene Deletion , Intracellular Signaling Peptides and Proteins , Liver X Receptors , Mice , Mice, Knockout , Neurodegenerative Diseases/drug therapy , Niemann-Pick C1 Protein , Niemann-Pick Diseases/drug therapy , Niemann-Pick Diseases/genetics , Orphan Nuclear Receptors , Pregnanolone/administration & dosage , Receptors, Cytoplasmic and Nuclear/agonists , Treatment OutcomeABSTRACT
Lysosomal storage diseases are a group of disorders caused by defects in enzymes responsible for degradation of particular compounds in lysosomes. In most cases, these diseases are fatal, and until recently no treatment was available. Introduction of enzyme replacement therapy was a breakthrough in the treatment of some of the diseases. However, while this therapy is effective in reduction of many somatic symptoms, its efficacy in the treatment of the central nervous system is negligible, if any, mainly because of problems with crossing the blood-brain-barrier by intravenously administered enzyme molecules. On the other hand, there are many lysosomal storage diseases in which the central nervous system is affected. Results of very recent studies indicate that in at least some cases, another type of therapy, called substrate deprivation therapy (or substrate reduction therapy) may be effective in the treatment of neuronopathic forms of lysosomal storage diseases. This therapy, based on inhibition of synthesis of the compounds that cannot be degraded in cells of the patients, has been shown to be effective in several animal models of various diseases, and recent reports demonstrate its efficacy in the treatment of patients suffering from Niemann-Pick C disease and Sanfilippo disease.
Subject(s)
Enzyme Inhibitors/therapeutic use , Lysosomal Storage Diseases/drug therapy , Mucopolysaccharidosis III/drug therapy , Niemann-Pick Diseases/drug therapy , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/therapeutic use , Animals , Gaucher Disease/drug therapy , Genistein/therapeutic use , Humans , Lysosomal Storage Diseases/metabolism , Lysosomal Storage Diseases/therapy , Lysosomes/metabolism , Sandhoff Disease/drug therapy , Tay-Sachs Disease/drug therapyABSTRACT
Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.