|
1
|
Wannemacher R, Jubran-Rudolf L, Zdora I, Leitzen E, Rohn K, Sippel V, Paschen C, Blattmann P, Baumgärtner W, Gerhauser I, Steiner MA. Sinbaglustat ameliorates disease pathology in a murine model of G M1 gangliosidosis without affecting CNS ganglioside levels. Neurobiol Dis 2025; 210:106917. [PMID: 40250720 DOI: 10.1016/j.nbd.2025.106917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/02/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025] Open
Abstract
Sinbaglustat is a brain-penetrating small molecule that inhibits the non-lysosomal glucocerebrosidase (GBA2) and, with lower potency, glucosylceramide synthase (GCS). Sinbaglustat has passed clinical phase I. Our preclinical study assessed its efficacy in a transgenic mouse model of GM1 gangliosidosis, lacking a functional β-galactosidase enzyme (Glb1-/-). Starting at 4 weeks of age, mice were either treated with a nominal dose of 10 or 300 mg/kg/day of sinbaglustat or remained untreated. Wild-type (WT) mice served as control. Body weight, clinical and neurological signs, and motor function was assessed until 17-18 weeks (4 months) and 30 weeks (7 months) of age when mice were euthanized for ex vivo assessments. In comparison to WT, Glb1-/- mice showed the expected accumulation of GM1 gangliosidosis-related sphingolipids, neuropathology, and behavioral deficits. Both dosages of sinbaglustat left GM1 and lyso GM1 levels in the brain unaffected but delayed the onset of motor impairment and progression of clinical disease in Glb1-/- mice with the higher dose being more efficacious. Histologically and immunohistochemically, both treatment groups of Glb1-/- mice displayed reduced neuronal vacuolation. Only the higher dose of sinbaglustat decreased axonal damage and astrogliosis, which was also associated with a decrease of the axonal/neuronal damage marker plasma neurofilament light at 4 months (17-18 weeks). Both doses of sinbaglustat increased the GBA2 substrate glucosylceramide (GluCer) in the brain, while only the high dose reduced GluCer and other glycosphingolipids (GSLs) in the periphery indicating additional inhibition of GCS. We conclude that sinbaglustat had a therapeutic-like effect in the GM1 gangliosidosis mouse model.
Collapse
Affiliation(s)
- Rouven Wannemacher
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Lorna Jubran-Rudolf
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Isabel Zdora
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany
| | - Eva Leitzen
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | - Karl Rohn
- Department of Biometry, Epidemiology and Data processing, University of Veterinary Medicine Hannover, Bünteweg 12, 30559 Hannover, Germany
| | - Virginie Sippel
- Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Christoph Paschen
- Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Peter Blattmann
- Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
| | - Ingo Gerhauser
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany
| | | |
Collapse
|
|
2
|
Xu K, Yang M, Guan L, Yang C, Qiao L, Li Y, Lin J, Li X. Therapeutic Potential of Mesenchymal Stem Cells in Niemann-Pick Disease. Mol Biotechnol 2025:10.1007/s12033-025-01435-3. [PMID: 40281376 DOI: 10.1007/s12033-025-01435-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 04/03/2025] [Indexed: 04/29/2025]
Abstract
Niemann-Pick disease (NPD) is a rare autosomal recessive neurodegenerative disease characterized by hepatosplenomegaly, neuropathy, and a significantly shortened lifespan. Lipid metabolism disorder is the main pathological feature of NPD. Currently, the exact pathogenesis of NPD remains unclear, and drug therapy is largely palliative, focusing on symptom management, but it has side effects. Mesenchymal stem cells (MSCs) possess several advantageous properties, including their differentiation potential, wide availability, low immunogenicity, and the ability to secrete regulatory factors, which have led to their extensive application in basic research targeting neurodegenerative diseases. Studies have demonstrated that transplantation of MSCs from different sources into animal models of NPD can delay the loss of Purkinje cells in the cerebellum, reduce lipid deposition, improve motor coordination, slow the rate of weight loss, and extend lifespan. This review explores the therapeutic potential of MSCs in the treatment of NPD, highlighting their emerging role in addressing this challenging condition.
Collapse
Affiliation(s)
- Keli Xu
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Minlin Yang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lihong Guan
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Ciqing Yang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Liang Qiao
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Yonghai Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Juntang Lin
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan International Joint Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Xiaoying Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| |
Collapse
|
|
3
|
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. eLife 2025; 13:RP103137. [PMID: 40184172 PMCID: PMC11970905 DOI: 10.7554/elife.103137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025] Open
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Collapse
Affiliation(s)
- Kaili Du
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
- Department of Molecular, Cellular, and Developmental Biology, University of MichiganAnn ArborUnited States
| | - Hongyu Chen
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Zhaonan Pan
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Mengli Zhao
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Shixue Cheng
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Yu Luo
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Wenhe Zhang
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
| | - Dan Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of TechnologyHangzhouChina
- Department of Molecular, Cellular, and Developmental Biology, University of MichiganAnn ArborUnited States
| |
Collapse
|
|
4
|
Byrne BJ, Parenti G, Schoser B, van der Ploeg AT, Do H, Fox B, Goldman M, Johnson FK, Kang J, Mehta N, Mondick J, Sheikh MO, Sitaraman Das S, Tuske S, Brudvig J, Weimer JM, Mozaffar T. Cipaglucosidase alfa plus miglustat: linking mechanism of action to clinical outcomes in late-onset Pompe disease. Front Neurol 2024; 15:1451512. [PMID: 39494167 PMCID: PMC11527667 DOI: 10.3389/fneur.2024.1451512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 09/24/2024] [Indexed: 11/05/2024] Open
Abstract
Enzyme replacement therapy (ERT) is the only approved disease-modifying treatment modality for Pompe disease, a rare, inherited metabolic disorder caused by a deficiency in the acid α-glucosidase (GAA) enzyme that catabolizes lysosomal glycogen. First-generation recombinant human GAA (rhGAA) ERT (alglucosidase alfa) can slow the progressive muscle degeneration characteristic of the disease. Still, most patients experience diminished efficacy over time, possibly because of poor uptake into target tissues. Next-generation ERTs aim to address this problem by increasing bis-phosphorylated high mannose (bis-M6P) N-glycans on rhGAA as these moieties have sufficiently high receptor binding affinity at the resultant low interstitial enzyme concentrations after dosing to drive uptake by the cation-independent mannose 6-phosphate receptor on target cells. However, some approaches introduce bis-M6P onto rhGAA via non-natural linkages that cannot be hydrolyzed by natural human enzymes and thus inhibit the endolysosomal glycan trimming necessary for complete enzyme activation after cell uptake. Furthermore, all rhGAA ERTs face potential inactivation during intravenous delivery (and subsequent non-productive clearance) as GAA is an acid hydrolase that is rapidly denatured in the near-neutral pH of the blood. One new therapy, cipaglucosidase alfa plus miglustat, is hypothesized to address these challenges by combining an enzyme enriched with naturally occurring bis-M6P N-glycans with a small-molecule stabilizer. Here, we investigate this hypothesis by analyzing published and new data related to the mechanism of action of the enzyme and stabilizer molecule. Based on an extensive collection of in vitro, preclinical, and clinical data, we conclude that cipaglucosidase alfa plus miglustat successfully addresses each of these challenges to offer meaningful advantages in terms of pharmacokinetic exposure, target-cell uptake, endolysosomal processing, and clinical benefit.
Collapse
Affiliation(s)
- Barry J. Byrne
- Department of Pediatrics in the College of Medicine, University of Florida, Gainesville, FL, United States
| | - Giancarlo Parenti
- Metabolic Unit, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Benedikt Schoser
- Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
| | | | - Hung Do
- M6P-Therapeutics, St Louis, MO, United States
| | - Brian Fox
- Amicus Therapeutics, Inc., Princeton, NJ, United States
| | | | | | - Jia Kang
- Metrum Research Group, Tariffville, CT, United States
| | - Nickita Mehta
- Amicus Therapeutics, Inc., Princeton, NJ, United States
| | - John Mondick
- Incyte Corporation, Wilmington, DE, United States
| | | | | | - Steven Tuske
- Amicus Therapeutics, Inc., Princeton, NJ, United States
| | - Jon Brudvig
- Amicus Therapeutics, Inc., Princeton, NJ, United States
| | | | - Tahseen Mozaffar
- Department of Neurology, University of California, Irvine, Irvine, CA, United States
| |
Collapse
|
|
5
|
Solomon BI, Muñoz AM, Sinaii N, Mohamed H, Farhat NM, Alexander D, Do AD, Porter FD. Swallowing characterization of adult-onset Niemann-Pick, type C1 patients. Orphanet J Rare Dis 2024; 19:231. [PMID: 38863022 PMCID: PMC11165794 DOI: 10.1186/s13023-024-03241-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk. This study aims to characterize swallowing function in AO NPC1, addressing the gap in understanding and clinical management. METHODS Fourteen AO NPC1 individuals in a prospective natural history study (NCT00344331) underwent comprehensive assessments, including history and physical examinations utilizing the NPC1 severity rating scale, videofluoroscopic swallowing studies with summary interpretive analysis, and cerebrospinal fluid (CSF) collection for biomarker evaluation at baseline visit. Descriptive statistics and multivariate statistical modeling were employed to analyze NPC1 disease covariates, along with the American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH Penetration Aspiration Scale (NIH-PAS). RESULTS Our cohort, comprised of 14 predominately female (n = 11, 78.6%) individuals, had an average age of 43.1 ± 16.7 years at the initial visit. Overall, our AO patients were able to swallow independently with no/minimal cueing, with 6 (43%) avoiding specific food items or requiring more time. Upon risk analysis of aspiration, the cohort demonstrated no obvious aspiration risk or laryngeal aspiration in 8 (57%), minimal risk with intermittent laryngeal penetration and retrograde excursion in 5(36%), and moderate risk (7%) in only one. Dietary modifications were recommended in 7 (50%), particularly for liquid viscosities (n = 6, 43%) rather than solids (n = 3, 21%). No significant correlations were identified between swallowing outcomes and NPC1-related parameters or CSF biomarkers. CONCLUSION Despite the heterogeneity in NPC1 presentation, the AO cohort displayed functional swallowing abilities with low aspiration risk with some participants still requiring some level of dietary modifications. This study emphasizes the importance of regular swallowing evaluations and management in AO NPC1 to address potential morbidities associated with dysphagia such as aspiration. These findings provide clinical recommendations for the assessment and management of the AO cohort, contributing to improved care for these individuals.
Collapse
Affiliation(s)
- Beth I Solomon
- Speech-Language Pathology Section, Mark O. Hatfield Clinical Center, National Institutes of Health, Bethesda, MD, USA.
| | - Andrea M Muñoz
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Ninet Sinaii
- Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Hibaaq Mohamed
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Nicole M Farhat
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Derek Alexander
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - An Dang Do
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Forbes D Porter
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
6
|
Hosseini K, Fallahi J, Razban V, Sirat RZ, Varasteh M, Tarhriz V. Overview of clinical, molecular, and therapeutic features of Niemann-Pick disease (types A, B, and C): Focus on therapeutic approaches. Cell Biochem Funct 2024; 42:e4028. [PMID: 38715125 DOI: 10.1002/cbf.4028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 04/16/2024] [Accepted: 04/25/2024] [Indexed: 06/30/2024]
Abstract
Niemann-Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1, NPC1, and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.
Collapse
Affiliation(s)
- Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahid Razban
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Vahideh Tarhriz
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| |
Collapse
|
|
7
|
Maekawa M. Analysis of Metabolic Changes in Endogenous Metabolites and Diagnostic Biomarkers for Various Diseases Using Liquid Chromatography and Mass Spectrometry. Biol Pharm Bull 2024; 47:1087-1105. [PMID: 38825462 DOI: 10.1248/bpb.b24-00073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Analysis of endogenous metabolites in various diseases is useful for searching diagnostic biomarkers and elucidating the molecular mechanisms of pathophysiology. The author and collaborators have developed some LC/tandem mass spectrometry (LC/MS/MS) methods for metabolites and applied them to disease-related samples. First, we identified urinary conjugated cholesterol metabolites and serum N-palmitoyl-O-phosphocholine serine as useful biomarkers for Niemann-Pick disease type C (NPC). For the purpose of intraoperative diagnosis of glioma patients, we developed the LC/MS/MS analysis methods for 2-hydroxyglutaric acid or cystine and found that they could be good differential biomarkers. For renal cell carcinoma, we searched for various biomarkers for early diagnosis, malignancy evaluation and recurrence prediction by global metabolome analysis and targeted LC/MS/MS analysis. In pathological analysis, we developed a simultaneous LC/MS/MS analysis method for 13 steroid hormones and applied it to NPC cells, we found 6 types of reductions in NPC model cells. For non-alcoholic steatohepatitis (NASH), model mice were prepared with special diet and plasma bile acids were measured, and as a result, hydrophilic bile acids were significantly increased. In addition, we developed an LC/MS/MS method for 17 sterols and analyzed liver cholesterol metabolites and found a decrease in phytosterols and cholesterol synthetic markers and an increase in non-enzymatic oxidative sterols in the pre-onset stage of NASH. We will continue to challenge themselves to add value to clinical practice based on cutting-edge analytical chemistry methodology.
Collapse
|
|
8
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
9
|
Yasuda T, Uchiyama T, Watanabe N, Ito N, Nakabayashi K, Mochizuki H, Onodera M. Peripheral immune system modulates Purkinje cell degeneration in Niemann-Pick disease type C1. Life Sci Alliance 2023; 6:e202201881. [PMID: 37369603 PMCID: PMC10300197 DOI: 10.26508/lsa.202201881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM-derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
Collapse
Affiliation(s)
- Toru Yasuda
- Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
| | - Toru Uchiyama
- Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
| | - Nobuyuki Watanabe
- Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
| | - Noriko Ito
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
| | - Hideki Mochizuki
- Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masafumi Onodera
- Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
| |
Collapse
|
|
10
|
Las Heras M, Szenfeld B, Ballout RA, Buratti E, Zanlungo S, Dardis A, Klein AD. Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine. NPJ Genom Med 2023; 8:21. [PMID: 37567876 PMCID: PMC10421955 DOI: 10.1038/s41525-023-00365-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.
Collapse
Affiliation(s)
- Macarena Las Heras
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, 7780272, Chile
| | - Benjamín Szenfeld
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, 7780272, Chile
| | - Rami A Ballout
- Department of Pediatrics, University of Texas Southwestern (UTSW) Medical Center and Children's Health, Dallas, TX, 75235, USA
| | - Emanuele Buratti
- Molecular Pathology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, 34149, Italy
| | - Silvana Zanlungo
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, 8330033, Chile
| | - Andrea Dardis
- Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100, Udine, Italy
| | - Andrés D Klein
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, 7780272, Chile.
| |
Collapse
|
|
11
|
Freihuber C, Dahmani-Rabehi B, Brassier A, Broué P, Cances C, Chabrol B, Eyer D, Labarthe F, Latour P, Levade T, Pichard S, Sevin C, Vanier MT, Héron B. Effects of miglustat therapy on neurological disorder and survival in early-infantile Niemann-Pick disease type C: a national French retrospective study. Orphanet J Rare Dis 2023; 18:204. [PMID: 37480097 PMCID: PMC10362619 DOI: 10.1186/s13023-023-02804-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients. METHODS Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded. RESULTS Ten patients were included in the treated group (year of birth: 2006-2012), and 16 patients in the untreated group [born 1987-2005 (n = 15), 2012 (n = 1)]. The median age at neurological onset was 9 months (5-18) in the treated group, and 12 months (3-18) in the untreated group (p = 0.22). Miglustat therapy was started at a median age of 24.5 months (9-29) and median duration was 30 months (11-56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p = 0.11). CONCLUSIONS Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C.
Collapse
Affiliation(s)
- Cécile Freihuber
- Department of Paediatric Neurology, Reference Centre for Lysosomal Diseases, Armand Trousseau-La Roche Guyon Hospital and Hospital-University I2-D2 Federation, Sorbonne-Université, Paris, France
| | | | - Anaïs Brassier
- Department of Metabolic Disorders, Reference Center for Inborn Errors of Metabolism, Necker-Enfants Malades University Hospital, Paris, France
| | - Pierre Broué
- Department of Paediatric Hepatology and Metabolic Disorders, Reference Centre for Inborn Errors of Metabolism and Genetic Cholestasis, Children's Hospital Toulouse University Hospitals, Toulouse, France
| | - Claude Cances
- Department of Paediatric Neurology, Purpan University Hospital, Toulouse, France
| | - Brigitte Chabrol
- Department of Paediatric Neurometabolism, La Timone University Hospital, Marseille, France
| | - Didier Eyer
- Department of Paediatrics, Haguenau Hospital, Hagueneau, France
| | - François Labarthe
- CRMR ToTeM, Department of Pediatrics, Hôpital Clocheville, CHRU Tours, and Laboratoire N2C, Inserm U1069, Université François Rabelais de Tours, 37 000, Tours, France
| | - Philippe Latour
- Department of Biochemistry and Molecular Biology, Hospices Civils de Lyon, Lyon, France
| | - Thierry Levade
- INSERM U1037 (Cancer Research Centre of Toulouse), Université Paul Sabatier, Toulouse, France
- Department of Clinical Biochemistry, Toulouse University Hospital, Toulouse, France
| | - Samia Pichard
- Department of Metabolic Disorders, Reference Center for Inborn Errors of Metabolism, Necker-Enfants Malades University Hospital, Paris, France
| | - Caroline Sevin
- Department of Paediatric Neurology, Kremlin-Bicêtre University Hospital, Paris, France
| | - Marie T Vanier
- Laboratoire Gillet-Mérieux, Lyon-East University Hospital, Hospices Civils de Lyon, Lyon, France
- INSERM U820, Lyon, France
| | - Bénédicte Héron
- Department of Paediatric Neurology, Reference Centre for Lysosomal Diseases, Armand Trousseau-La Roche Guyon Hospital and Hospital-University I2-D2 Federation, Sorbonne-Université, Paris, France.
| |
Collapse
|
|
12
|
Bremova-Ertl T, Schneider S. Current advancements in therapy for Niemann-Pick disease: progress and pitfalls. Expert Opin Pharmacother 2023; 24:1229-1247. [PMID: 37211769 DOI: 10.1080/14656566.2023.2215386] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
INTRODUCTION Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder. To combat the progressive neurodegeneration in NPC, disease-modifying treatment needs to be introduced early in the course of the disease. The only approved, disease-modifying treatment is a substrate-reduction treatment, miglustat. Given miglustat's limited efficacy, new compounds are under development, including gene therapy; however, many are still far from clinical use. Moreover, the phenotypic heterogeneity and variable course of the disease can impede the development and approval of new agents. AREAS COVERED Here, we offer an expert review of these therapeutic candidates, with a broad scope not only on the main pharmacotherapies, but also on experimental approaches, gene therapies, and symptomatic strategies. The National Institute of Health (NIH) database PubMed has been searched for the combination of the words 'Niemann-Pick type C'+ 'treatment' or 'therapy' or 'trial.' The website clinicaltrials.gov has also been consulted. EXPERT OPINION We conclude a combination of treatment strategies should be sought, with a holistic approach, to improve the quality of life of affected individuals and their families.
Collapse
Affiliation(s)
- Tatiana Bremova-Ertl
- Department of Neurology, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland
- Center for Rare Diseases, University Hospital Bern (Inselspital) and University of Bern, Bern, Switzerland
| | - Susanne Schneider
- Department of Neurology, Ludwig-Maximilians-University, Munich, Germany
| |
Collapse
|
|
13
|
Pfrieger FW. The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism. Prog Lipid Res 2023; 90:101225. [PMID: 37003582 DOI: 10.1016/j.plipres.2023.101225] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
Collapse
|
|
14
|
Organ Weights in NPC1 Mutant Mice Partly Normalized by Various Pharmacological Treatment Approaches. Int J Mol Sci 2022; 24:ijms24010573. [PMID: 36614015 PMCID: PMC9820376 DOI: 10.3390/ijms24010573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/14/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022] Open
Abstract
Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the NPC1 leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-Npc1m1N/-J Jackson Npc1 mice in female and male Npc1+/+ and Npc1-/- mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 Npc1+/+, 175 Npc1-/-) were dissected at P65. In both sexes, the body weights of None and Sham Npc1-/- mice were lower than those of respective Npc1+/+ mice. The influence of the Npc1 mutation and/or sex on the weights of various organs, however, differed considerably. In males, Npc1+/+ and Npc1-/- mice had comparable absolute weights of lungs, spleen, and adrenal glands. In Npc1-/- mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female Npc1-/- mice, ovaries, and uteri were significantly smaller. In Npc1-/- mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies.
Collapse
|
|
15
|
Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022; 14:1844-1861. [PMID: 36340750 PMCID: PMC9627439 DOI: 10.4254/wjh.v14.i10.1844] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/21/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
Collapse
Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad 500072, India
| |
Collapse
|
|
16
|
Gutić M, Milosavljević MN, Janković SM. Cost-effectiveness of miglustat versus symptomatic therapy of Niemann-Pick disease type C. Int J Clin Pharm 2022; 44:1442-1453. [PMID: 36243834 DOI: 10.1007/s11096-022-01491-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Niemann-Pick disease type C (NP-C) is a progressive neurodegenerative disorder with early infantile (< 2 years), late infantile (2-6 years), juvenile (7-15 years) and adolescent (> 15 years) onset. The mainstay of therapy for NP-C patients with neurological symptoms is miglustat, a drug that may modify the course of the disease. AIM Our aim was to evaluate the cost-effectiveness of miglustat in comparison to symptomatic therapy in patients with NP-C in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. METHOD The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was eighty years. The main outcomes of the study were quality-adjusted life years gained with miglustat and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Discrete-Event Simulation model. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. RESULTS Treatment with miglustat was not cost-effective when compared with symptomatic therapy and was associated with negative values of net monetary benefit regardless of the onset of neurological manifestations (- 110,447,627.00 ± 701,614.00 RSD, - 343,871,695.00 ± 2,577,441.00 RSD, - 1,397,908,502.00 ± 23,084,235.00 RSD and - 2,953,680,879.00 ± 33,297,412.00 RSD) for early infantile, late infantile, juvenile and adolescent cohorts, respectively). CONCLUSION When traditional pharmacoeconomic evaluation is employed, miglustat is not a cost-effective option in comparison to symptomatic therapy for the treatment of NP-C. However, given the proven efficacy of miglustat, there is a need to find ways to make this drug available to all patients with NP-C.
Collapse
Affiliation(s)
- Medo Gutić
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000, Kragujevac, Serbia
| | - Miloš N Milosavljević
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000, Kragujevac, Serbia.
| | - Slobodan M Janković
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000, Kragujevac, Serbia
| |
Collapse
|
|
17
|
Cao X, Du X, Jiao H, An Q, Chen R, Fang P, Wang J, Yu B. Carbohydrate-based drugs launched during 2000 -2021. Acta Pharm Sin B 2022; 12:3783-3821. [PMID: 36213536 PMCID: PMC9532563 DOI: 10.1016/j.apsb.2022.05.020] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023] Open
Abstract
Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense systems, and forming antibiotics secondary metabolites. The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases. During 2000 to 2021, totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents. Here we provide a comprehensive review on the chemical structures, activities, and clinical trial results of these carbohydrate-based drugs, which are categorized by their indications into antiviral drugs, antibacterial/antiparasitic drugs, anticancer drugs, antidiabetics drugs, cardiovascular drugs, nervous system drugs, and other agents.
Collapse
Affiliation(s)
- Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Xiaojing Du
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Heng Jiao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Quanlin An
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ruoxue Chen
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Pengfei Fang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Jing Wang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| |
Collapse
|
|
18
|
Lu B, Ku J, Flojo R, Olson C, Bengford D, Marriott G. Exosome- and extracellular vesicle-based approaches for the treatment of lysosomal storage disorders. Adv Drug Deliv Rev 2022; 188:114465. [PMID: 35878794 DOI: 10.1016/j.addr.2022.114465] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 06/22/2022] [Accepted: 07/19/2022] [Indexed: 12/16/2022]
Abstract
Cell-generated extracellular vesicles (EVs) are being engineered as biologically-inspired vehicles for targeted delivery of therapeutic agents to treat difficult-to-manage human diseases, including lysosomal storage disorders (LSDs). Engineered EVs offer distinct advantages for targeted delivery of therapeutics compared to existing synthetic and semi-synthetic nanoscale systems, for example with regard to their biocompatibility, circulation lifetime, efficiencies in delivery of drugs and biologics to target cells, and clearance from the body. Here, we review literature related to the design and preparation of EVs as therapeutic carriers for targeted delivery and therapy of drugs and biologics with a focus on LSDs. First, we introduce the basic pathophysiology of LDSs and summarize current approaches to diagnose and treat LSDs. Second, we will provide specific details about EVs, including subtypes, biogenesis, biological properties and their potential to treat LSDs. Third, we review state-of-the-art approaches to engineer EVs for treatments of LSDs. Finally, we summarize explorative basic research and applied applications of engineered EVs for LSDs, and highlight current challenges, and new directions in developing EV-based therapies and their potential impact on clinical medicine.
Collapse
Affiliation(s)
- Biao Lu
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Joy Ku
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Renceh Flojo
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Chris Olson
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - David Bengford
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Gerard Marriott
- Department of Bioengineering, University of California at Berkeley, California 94720, USA.
| |
Collapse
|
|
19
|
Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems. Cells 2022; 11:cells11030319. [PMID: 35159129 PMCID: PMC8834315 DOI: 10.3390/cells11030319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open
Abstract
Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes and lysosomes. Pharmacological chaperones (PCs) are described to protect misfolded proteins from proteasomal degradation and are being discussed as a treatment strategy for NP-C1. Here, we used a combinatorial approach of high-throughput in silico screening of FDA-approved drugs and in vitro biochemical assays to identify potential PCs. The effects of the hit compounds identified by molecular docking were compared in vitro with 25-hydroxycholesterol (25-HC), which is known to act as a PC for NP-C1. We analyzed cholesterol accumulation, NPC1 protein content, and lysosomal localization in patient-specific fibroblasts, as well as in neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSCs). One compound, namely abiraterone acetate, showed comparable results to 25-HC and restored NPC1 protein level, corrected the intracellular localization of NPC1, and consequently decreased cholesterol accumulation in NPC1-mutated fibroblasts and iPSC-derived neural differentiated and hepatocyte-like cells. The discovered PC altered not only the pathophysiological phenotype of cells carrying the I1061T mutation— known to be responsive to treatment with PCs—but an effect was also observed in cells carrying other NPC1 missense mutations. Therefore, we hypothesize that the PCs studied here may serve as an effective treatment strategy for a large group of NP-C1 patients.
Collapse
|
|
20
|
Sitarska D, Tylki-Szymańska A, Ługowska A. Treatment trials in Niemann-Pick type C disease. Metab Brain Dis 2021; 36:2215-2221. [PMID: 34596813 PMCID: PMC8580890 DOI: 10.1007/s11011-021-00842-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/14/2021] [Indexed: 10/28/2022]
Abstract
Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood-brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.
Collapse
Affiliation(s)
- Dominika Sitarska
- Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957, Warsaw, Poland.
| | - Anna Tylki-Szymańska
- Department of Pediatric Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, 04-730, Warsaw, Poland
| | - Agnieszka Ługowska
- Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957, Warsaw, Poland.
| |
Collapse
|
|
21
|
Estimated prevalence of Niemann-Pick type C disease in Quebec. Sci Rep 2021; 11:22621. [PMID: 34799641 PMCID: PMC8604933 DOI: 10.1038/s41598-021-01966-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/08/2021] [Indexed: 12/30/2022] Open
Abstract
Niemann–Pick type C (NP-C) disease is an autosomal recessive disease caused by variants in the NPC1 or NPC2 genes. It has a large range of symptoms depending on age of onset, thus making it difficult to diagnose. In adults, symptoms appear mainly in the form of psychiatric problems. The prevalence varies from 0.35 to 2.2 per 100,000 births depending on the country. The aim of this study is to calculate the estimated prevalence of NP-C in Quebec to determine if it is underdiagnosed in this population. The CARTaGENE database is a unique database that regroups individuals between 40 and 69 years old from metropolitan regions of Quebec. RNA-sequencing data was available for 911 individuals and exome sequencing for 198 individuals. We used a bioinformatic pipeline on those individuals to extract the variants in the NPC1/2 genes. The prevalence in Quebec was estimated assuming Hardy–Weinberg Equilibrium. Two pathogenic variants were used. The variant p.Pro543Leu was found in three heterozygous individuals that share a common haplotype, which suggests a founder French-Canadian pathogenic variant. The variant p.Ile1061Thr was found in two heterozygous individuals. Both variants have previously been reported and are usually associated with infantile onset. The estimated prevalence calculated using those two variants is 0.61:100,000 births. This study represents the first estimate of NP-C in Quebec. The estimated prevalence for NP-C is likely underestimated due to misdiagnosis or missed cases. It is therefore important to diagnose all NP-C patients to initiate early treatment.
Collapse
|
|
22
|
Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki‐Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, í Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis 2021; 44:1463-1480. [PMID: 34418116 PMCID: PMC9293014 DOI: 10.1002/jimd.12428] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 08/11/2021] [Accepted: 08/19/2021] [Indexed: 12/13/2022]
Abstract
Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.
Collapse
Affiliation(s)
- Eugen Mengel
- SphinCS GmbHInstitute of Clinical Science for LSDHochheimGermany
| | - Marc C. Patterson
- Departments of Neurology, Pediatrics and Medical GeneticsMayo ClinicRochesterMinnesotaUSA
| | - Rosalia M. Da Riol
- Regional Coordination Center for Rare DiseasesAcademic Hospital ‘Santa Maria della Misericordia’UdineItaly
| | - Mireia Del Toro
- Pediatric Neurology DepartmentVall d'Hebron University HospitalBarcelonaSpain
| | - Federica Deodato
- Division of MetabolismOspedale Pediatrico Bambino Gesù, IRCCSRomeItaly
| | - Matthias Gautschi
- Department of Paediatrics, Division of Endocrinology, Diabetology and Metabolism, and Institute of Clinical Chemistry, InselspitalUniversity Hospital Bern, University of BernBernSwitzerland
| | - Stephanie Grunewald
- Department of Metabolic MedicineGreat Ormond Street Hospital, Institute of Child Health, UCL, NIHR Biomedical Research CenterLondonUK
| | - Sabine Grønborg
- Centre for Inherited Metabolic DiseasesCopenhagen University Hospital (Rigshospitalet)CopenhagenDenmark
| | - Paul Harmatz
- Gastroenterology and HepatologyUCSF Benioff Children's Hospital OaklandOaklandCaliforniaUSA
| | - Bénédicte Héron
- Department of Pediatric Neurology, Reference Centre for Lysosomal DiseasesUniversity Hospital Armand TrousseauParisFrance
| | - Esther M. Maier
- Department of Inborn Errors of MetabolismUniversity of Munich Children's HospitalMunichGermany
| | - Agathe Roubertie
- Department of NeuropediatricsCentre Hospitalier Universitaire de MontpellierMontpellierFrance
| | - Saikat Santra
- Department of Inherited Metabolic DisordersBirmingham Children's HospitalBirminghamUK
| | - Anna Tylki‐Szymanska
- Department of Paediatrics, Nutrition and Metabolic DiseasesThe Children's Memorial InstituteWarsawPoland
| | - Simon Day
- BiostatisticsClinical Trials Consulting & Training LimitedBuckinghamUK
| | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Budani M, Auray-Blais C, Lingwood C. ATP-binding cassette transporters mediate differential biosynthesis of glycosphingolipid species. J Lipid Res 2021; 62:100128. [PMID: 34597626 PMCID: PMC8569594 DOI: 10.1016/j.jlr.2021.100128] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 08/18/2021] [Accepted: 09/03/2021] [Indexed: 01/13/2023] Open
Abstract
The cytosolic-oriented glucosylceramide (GlcCer) synthase is enigmatic, requiring nascent GlcCer translocation to the luminal Golgi membrane to access glycosphingolipid (GSL) anabolic glycosyltransferases. The mechanism by which GlcCer is flipped remains unclear. To investigate the role of GlcCer-binding partners in this process, we previously made cleavable, biotinylated, photoreactive GlcCer analogs in which the reactive nitrene was closely apposed to the GlcCer head group, while maintaining a C16-acyl chain. GlcCer-binding protein specificity was validated for both photoprobes. Using one probe, XLB, here we identified ATP-binding cassette (ABC) transporters ABCA3, ABCB4, and ABCB10 as unfractionated microsomal GlcCer-binding proteins in DU-145 prostate tumor cells. siRNA knockdown (KD) of these transporters differentially blocked GSL synthesis assessed in toto and via metabolic labeling. KD of ABCA3 reduced acid/neutral GSL levels, but increased those of LacCer, while KD of ABCB4 preferentially reduced neutral GSL levels, and KD of ABCB10 reduced levels of both neutral and acidic GSLs. Depletion of ABCA12, implicated in GlcCer transport, preferentially decreased neutral GSL levels, while ABCB1 KD preferentially reduced gangliosides, but increased neutral GSL Gb3. These results imply that multiple ABC transporters may provide distinct but overlapping GlcCer and LacCer pools within the Golgi lumen for anabolism of different GSL series by metabolic channeling. Differential ABC family member usage may fine-tune GSL biosynthesis depending on cell/tissue type. We conclude that ABC transporters provide a new tool for the regulation of GSL biosynthesis and serve as potential targets to reduce selected GSL species/subsets in diseases in which GSLs are dysregulated.
Collapse
Affiliation(s)
- Monique Budani
- Division of Molecular Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Christiane Auray-Blais
- Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Clifford Lingwood
- Division of Molecular Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
24
|
Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol 2021; 77:1564-1568. [PMID: 32897301 DOI: 10.1001/jamaneurol.2020.3241] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally. Objective To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1. Design, Setting, and Participants Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019. Exposures Oral miglustat at baseline and at follow-up. Main Outcomes and Measures Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively. Results Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29). Conclusions and Relevance These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.
Collapse
Affiliation(s)
- Beth I Solomon
- Speech-Language Pathology Section, Rehabilitation Medicine Department, Mark O. Hatfield Clinical Center, Bethesda, Maryland
| | - Andrew C Smith
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Ninet Sinaii
- Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Nicole Farhat
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Monique C King
- Speech-Language Pathology Section, Rehabilitation Medicine Department, Mark O. Hatfield Clinical Center, Bethesda, Maryland
| | - Leonza Machielse
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Forbes D Porter
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
| |
Collapse
|
|
25
|
Cariati I, Masuelli L, Bei R, Tancredi V, Frank C, D’Arcangelo G. Neurodegeneration in Niemann-Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment. Int J Mol Sci 2021; 22:ijms22126600. [PMID: 34202978 PMCID: PMC8234817 DOI: 10.3390/ijms22126600] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 01/08/2023] Open
Abstract
Niemann–Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.
Collapse
Affiliation(s)
- Ida Cariati
- Medical-Surgical Biotechnologies and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome “Sapienza”, Viale Regina Elena 324, 00161 Rome, Italy;
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
| | - Virginia Tancredi
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
- Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
| | - Claudio Frank
- UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy;
| | - Giovanna D’Arcangelo
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
- Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
- Correspondence:
| |
Collapse
|
|
26
|
Han S, Zhang H, Yi M, Liu X, Maegawa GHB, Zou Y, Wang Q, Wu D, Ye Z. Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1. Front Pharmacol 2021; 12:667361. [PMID: 34177581 PMCID: PMC8220070 DOI: 10.3389/fphar.2021.667361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/25/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer's disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1. Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety. Results: Of the 13 patients with NP-C1 (12-33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium. Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding. Clinical Trial Registration: ClinicalTrials.gov, NCT03201627.
Collapse
Affiliation(s)
- Shiqian Han
- Department of Tropical Medicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huiwen Zhang
- Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengni Yi
- Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoqing Liu
- Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gustavo H B Maegawa
- Department of Pediatrics, Genetics and Metabolism, University of Florida, Gainesville, FL, United States
| | - Yunding Zou
- Department of Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qijun Wang
- Department of Gastroenterology of Ruijin Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Departments of Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, United States.,Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
| | - Dianqing Wu
- Departments of Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, United States.,Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
| | - Zhijia Ye
- Department of Tropical Medicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China.,Laboratory Animal Research Center, Chongqing University School of Medicine, Chongqing, China
| |
Collapse
|
|
27
|
Holzmann C, Witt M, Rolfs A, Antipova V, Wree A. Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1. Int J Mol Sci 2021; 22:ijms22052539. [PMID: 33802605 PMCID: PMC7962008 DOI: 10.3390/ijms22052539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/16/2022] Open
Abstract
In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1−/− mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1−/− and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1−/− mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1−/− mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1−/− mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1−/− mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1−/− mice was almost completely reduced only in the female groups.
Collapse
Affiliation(s)
- Carsten Holzmann
- Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany;
- Centre of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany;
| | - Martin Witt
- Centre of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany;
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany;
| | - Arndt Rolfs
- Centogene AG, Rostock, Am Strande 7, 18055 Rostock, Germany;
- University of Rostock, 18055 Rostock, Germany
| | - Veronica Antipova
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany;
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Macroscopic and Clinical Anatomy, Medical University of Graz, A-8010 Graz, Austria
| | - Andreas Wree
- Centre of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany;
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany;
- Correspondence: ; Tel.: +49-381-494-8429
| |
Collapse
|
|
28
|
Wang H, Shen Y, Zhao L, Ye Y. 1-Deoxynojirimycin and its Derivatives: A Mini Review of the Literature. Curr Med Chem 2021; 28:628-643. [PMID: 31942844 DOI: 10.2174/0929867327666200114112728] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/17/2019] [Accepted: 12/22/2019] [Indexed: 11/22/2022]
Abstract
1-Deoxynojirimycin (1-DNJ) is a naturally occurring sugar analogue with unique bioactivities. It is found in mulberry leaves and silkworms, as well as in the metabolites of certain microorganisms, including Streptomyces and Bacillus. 1-DNJ is a potent α-glucosidase inhibitor and it possesses anti-hyperglycemic, anti-obese, anti-viral and anti-tumor properties. Some derivatives of 1-DNJ, like miglitol, miglustat and migalastat, were applied clinically to treat diseases such as diabetes and lysosomal storage disorders. The present review focused on the extraction, determination, pharmacokinetics and bioactivity of 1-DNJ, as well as the clinical application of 1-DNJ derivatives.
Collapse
Affiliation(s)
- Haijun Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yin Shen
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Zhao
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Youfan Ye
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
29
|
Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C. Mol Genet Metab Rep 2021; 27:100723. [PMID: 33598405 PMCID: PMC7868989 DOI: 10.1016/j.ymgmr.2021.100723] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 01/17/2023] Open
Abstract
Background Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported. Case presentation We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness. Conclusion KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
Collapse
|
|
30
|
Völkner C, Liedtke M, Hermann A, Frech MJ. Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1. Int J Mol Sci 2021; 22:E710. [PMID: 33445799 PMCID: PMC7828283 DOI: 10.3390/ijms22020710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic symptoms, such as hepatosplenomegaly and pulmonary manifestations, the latter being particularly pronounced in NPC2 patients. NPC1 and NPC2 are rare diseases with the described neurovisceral clinical picture, but studies with human primary patient-derived neurons and hepatocytes are hardly feasible. Obviously, induced pluripotent stem cells (iPSCs) and their derivatives are an excellent alternative for indispensable studies with these affected cell types to study the multisystemic disease NPC1. Here, we present a review focusing on studies that have used iPSCs for disease modeling and drug discovery in NPC1 and draw a comparison to commonly used NPC1 models.
Collapse
Affiliation(s)
- Christin Völkner
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany; (C.V.); (M.L.); (A.H.)
| | - Maik Liedtke
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany; (C.V.); (M.L.); (A.H.)
| | - Andreas Hermann
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany; (C.V.); (M.L.); (A.H.)
- Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, 18147 Rostock, Germany
- German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, 18147 Rostock, Germany
| | - Moritz J. Frech
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany; (C.V.); (M.L.); (A.H.)
- Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, 18147 Rostock, Germany
| |
Collapse
|
|
31
|
Biomarker analysis of Niemann-Pick disease type C using chromatography and mass spectrometry. J Pharm Biomed Anal 2020; 191:113622. [PMID: 32998104 DOI: 10.1016/j.jpba.2020.113622] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/26/2020] [Accepted: 09/07/2020] [Indexed: 12/26/2022]
Abstract
Niemann-Pick disease type C (NPC) is an autosomal recessive disorder with progressive degradation of central nervous system. The age of the onset varies from perinatal to adulthood. Patients with NPC are affected in the central nervous system, peripheral nerves, and systemic organs. From these background, it is extremely difficult to discover NPC clinically and diagnose it correctly. The procedure of the conventional laboratory methods are complicated and it takes long time to obtain the result. Because of the importance of early treatments and the shortcomings of conventional diagnostic methods for NPC, remarkable attention has been paid to biomarkers and chemical diagnoses. In the last decade, many NPC biomarkers have been reported. They are classified as cholesterol-related metabolites, sphingolipid metabolites, and novel phospholipid metabolites, respectively. Therefore, these are all lipid metabolites. Various chemical analysis methods have been used for their identification. In addition, chromatography and mass spectrometry are mainly used for their quantification. This review article outlines NPC biomarkers reported in the last decade and their analytical methods.
Collapse
|
|
32
|
Gläser A, Hammerl F, Gräler MH, Coldewey SM, Völkner C, Frech MJ, Yang F, Luo J, Tönnies E, von Bohlen und Halbach O, Brandt N, Heimes D, Neßlauer AM, Korenke GC, Owczarek-Lipska M, Neidhardt J, Rolfs A, Wree A, Witt M, Bräuer AU. Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism. Int J Mol Sci 2020; 21:ijms21124502. [PMID: 32599915 PMCID: PMC7352403 DOI: 10.3390/ijms21124502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 12/17/2022] Open
Abstract
Niemann-Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1-/- mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1-/- mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1-/- mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.
Collapse
Affiliation(s)
- Anne Gläser
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany; (A.G.); (F.H.); (N.B.)
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
| | - Franziska Hammerl
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany; (A.G.); (F.H.); (N.B.)
| | - Markus H. Gräler
- Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany;
| | - Sina M. Coldewey
- Department of Anaesthesiology and Intensive Care Medicine, Septomics Research Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany;
| | - Christin Völkner
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany; (C.V.); (M.J.F.); (F.Y.); (J.L.)
| | - Moritz J. Frech
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany; (C.V.); (M.J.F.); (F.Y.); (J.L.)
- Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany
| | - Fan Yang
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany; (C.V.); (M.J.F.); (F.Y.); (J.L.)
| | - Jiankai Luo
- Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany; (C.V.); (M.J.F.); (F.Y.); (J.L.)
- Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany
| | - Eric Tönnies
- Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany; (E.T.); (O.v.B.u.H.)
| | - Oliver von Bohlen und Halbach
- Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany; (E.T.); (O.v.B.u.H.)
| | - Nicola Brandt
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany; (A.G.); (F.H.); (N.B.)
| | - Diana Heimes
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
| | - Anna-Maria Neßlauer
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
| | | | - Marta Owczarek-Lipska
- Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany; (M.O.-L.); (J.N.)
- Junior Research Group, Genetics of childhood brain malformations, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany
| | - John Neidhardt
- Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany; (M.O.-L.); (J.N.)
- Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany
| | | | - Andreas Wree
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
| | - Martin Witt
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
| | - Anja Ursula Bräuer
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany; (A.G.); (F.H.); (N.B.)
- Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany; (D.H.); (A.-M.N.); (A.W.); (M.W.)
- Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany
- Correspondence: ; Tel.: +49-441-798-3995
| |
Collapse
|
|
33
|
Lewis C, Keage M, Watanabe M, Schubiger D, Velakoulis D, Walterfang M, Vogel AP. Characterization of Dysphagia and Longitudinal Changes in Swallowing Function in Adults with Niemann-Pick Disease Type C Treated with Miglustat. Dysphagia 2020; 36:362-373. [PMID: 32562141 DOI: 10.1007/s00455-020-10145-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 06/06/2020] [Indexed: 11/26/2022]
Abstract
Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Miglustat is currently the only approved disease-specific treatment shown to be effective in stabilizing neurological symptoms. Miglustat has previously been reported to halt or improve early dysphagia and cognitive symptoms. Here we examine the characteristics of dysphagia, the relationship between dysphagia and the presence of cognitive impairment, and longitudinal changes in swallowing function during miglustat treatment in adult-and-adolescent-onset NPC. Retrospective analysis of videofluoroscopic swallow studies (VFSS) was completed for ten adults with NPC (mean age 28.44 years ± 9.34 years). Participants were recruited through the Royal Melbourne Hospital in Australia between 2008 and 2015. The Bethlehem Swallowing Scale and the Penetration-Aspiration Scale were used to quantify VFSS data. Dysphagia was present in 90% of participants at baseline with reduced lingual function and a delayed swallowing reflex as the most common symptoms. Swallow impairment appeared to stabilize during miglustat therapy for periods up to 66 months, with no significant changes in scores (p > 0.05). Data were in accordance with the literature and support the use of miglustat as an efficacious treatment for reducing swallowing impairment and stabilizing cognitive function. Findings provide detailed information on the impairments experienced by patients, give context to events leading to aspiration in NPC and, importantly, inform how management of dysphagia can complement pharmaceutical treatment.
Collapse
Affiliation(s)
- Courtney Lewis
- Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia
| | - Megan Keage
- Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia
| | - Miyuki Watanabe
- Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia
| | | | - Dennis Velakoulis
- Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, Australia
- Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia
| | - Mark Walterfang
- Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, Australia
- Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia
- Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
| | - Adam P Vogel
- Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia.
- Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
- Redenlab, Melbourne, Australia.
| |
Collapse
|
|
34
|
Leal AF, Espejo-Mojica AJ, Sánchez OF, Ramírez CM, Reyes LH, Cruz JC, Alméciga-Díaz CJ. Lysosomal storage diseases: current therapies and future alternatives. J Mol Med (Berl) 2020; 98:931-946. [PMID: 32529345 DOI: 10.1007/s00109-020-01935-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/28/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023]
Abstract
Lysosomal storage disorders (LSDs) are a group of monogenic diseases characterized by progressive accumulation of undegraded substrates into the lysosome, due to mutations in genes that encode for proteins involved in normal lysosomal function. In recent years, several approaches have been explored to find effective and successful therapies, including enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, hematopoietic stem cell transplantation, and gene therapy. In the case of gene therapy, genome editing technologies have opened new horizons to accelerate the development of novel treatment alternatives for LSD patients. In this review, we discuss the current therapies for this group of disorders and present a detailed description of major genome editing technologies, as well as the most recent advances in the treatment of LSDs. We will further highlight the challenges and current bioethical debates of genome editing.
Collapse
Affiliation(s)
- Andrés Felipe Leal
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Cra. 7 No. 43-82 Building 54, Room 305A, Bogotá D.C, 110231, Colombia
| | - Angela Johana Espejo-Mojica
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Cra. 7 No. 43-82 Building 54, Room 305A, Bogotá D.C, 110231, Colombia
| | - Oscar F Sánchez
- Neurobiochemistry and Systems Physiology, Biochemistry and Nutrition Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - Carlos Manuel Ramírez
- Department of Chemical and Food Engineering, Universidad de los Andes, Bogotá D.C., Colombia
| | - Luis Humberto Reyes
- Department of Chemical and Food Engineering, Universidad de los Andes, Bogotá D.C., Colombia
| | - Juan C Cruz
- Department of Biomedical Engineering, Universidad de los Andes, Bogotá D.C., Colombia
| | - Carlos Javier Alméciga-Díaz
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Cra. 7 No. 43-82 Building 54, Room 305A, Bogotá D.C, 110231, Colombia.
| |
Collapse
|
|
35
|
Patterson MC, Mengel E, Vanier MT, Moneuse P, Rosenberg D, Pineda M. Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry. Orphanet J Rare Dis 2020; 15:104. [PMID: 32334605 PMCID: PMC7183679 DOI: 10.1186/s13023-020-01363-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 03/18/2020] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Niemann-Pick disease Type C (NP-C) is a rare, progressive neurodegenerative disorder characterized by progressive neurodegeneration and premature death. We report data at closure of the NPC Registry that describes the natural history, disease course and treatment experience of NP-C patients in a real-world setting. METHODS The NPC Registry was a prospective observational cohort study that ran between September 2009 and October 2017. Patients with a confirmed diagnosis of NP-C were enrolled regardless of treatment status. All patients underwent clinical assessments and medical care as determined by their physicians; data were collected through a secure internet-based portal. RESULTS At closure on October 19, 2017, 472 patients from 22 countries were enrolled in the NPC Registry. Mean (standard deviation) age at enrollment was 21.2 (15.0) years, and 51.9% of patients were male. First neurological symptom onset occurred during the early-infantile (< 2 years), late-infantile (2 to < 6 years), juvenile (6 to < 15 years), or adolescent/adult (≥ 15 years) periods in 13.5, 25.6, 31.8, and 29.1% of cases, respectively. The most frequent neurological manifestations prior to enrollment included ataxia (67.9%), vertical supranuclear gaze palsy (67.4%), dysarthria (64.7%), cognitive impairment (62.7%), dysphagia (49.1%), and dystonia (40.2%). During infancy, splenomegaly and hepatomegaly were frequent (n = 199/398 [50%] and n = 147/397 [37.0%], respectively) and persisted in most affected patients. Of the 472 enrolled patients, 241 were continuously treated with miglustat during the NPC Registry observation period, of whom 172 of these 241 patients were treated continuously for ≥12 months. A composite disability score that assesses impairment of ambulation, manipulation, language, and swallowing was highest in the early-infantile population and lowest in the adolescent/adult population. Among the continuous miglustat therapy population, 70.5% of patients had improved or had stable disease (at least 3 of the 4 domains having a decreased or unchanged score between enrollment and last follow-up). The NPC Registry did not identify any new safety signals associated with miglustat therapy. CONCLUSIONS The profiles of clinical manifestations in the final NPC Registry dataset agreed with previous clinical descriptions. Miglustat therapy was associated with a stabilization of neurological manifestations in most patients. The safety and tolerability of miglustat therapy was consistent with previous reports.
Collapse
Affiliation(s)
- Marc C Patterson
- Department of Neurology, Mayo Clinic, 200 first Street SW, Rochester, MN, 55905, USA.
| | - Eugen Mengel
- Villa Metabolica, University of Mainz, Mainz, Germany.,Present Address: SphinCS GmbH, Hochheim, Germany
| | - Marie T Vanier
- INSERM Unit 820, Faculté de Médecine RTH Laennec, Lyon, France
| | - Patrick Moneuse
- Actelion Pharmaceuticals Ltd., A Janssen Pharmaceutical Company of Johnson & Johnson, Allschwil, Switzerland
| | - Daniel Rosenberg
- Actelion Pharmaceuticals Ltd., A Janssen Pharmaceutical Company of Johnson & Johnson, Allschwil, Switzerland
| | - Mercedes Pineda
- Institut Pediatric Hospital Sant Joan, Hospital Sant Joan de Déu, Passeig de Sant Joan de Deu, 2, 08950, Esplugues de Llobregat, Barcelona, Spain
| |
Collapse
|
|
36
|
Anheim M, Torres Martin JV, Kolb SA. Recessive Ataxia Differential Diagnosis Algorithm (RADIAL) Versus Specific Niemann-Pick Type C Suspicion Indices: A Retrospective Algorithm Comparison. CEREBELLUM (LONDON, ENGLAND) 2020; 19:243-251. [PMID: 31933160 DOI: 10.1007/s12311-020-01102-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Early diagnosis of Niemann-Pick disease type C (NPC) is crucial to slow the progression of neurological manifestations. Different tools were developed to aid diagnosis of NPC, but to date, no study has compared their performance. We aimed to compare the RADIAL algorithm, intended for the differential diagnosis of autosomal recessive cerebellar ataxias (ARCAs) and NPC-specific suspicion indices (SIs). This study was a retrospective analysis of data from 834 patients with molecularly confirmed ARCAs, including 57 NPC cases (RADIAL cohort). We aimed to compare the algorithm performance of RADIAL (Top 1 and Top 3) with that of four SIs (Original, Refined, 2/3 and 2/7) in discriminating NPC cases and non-NPC cases. We also identified ARCAs closely related to NPC as those with low specificity to detect non-NPC cases and described differential and overlapping features with NPC. Overall, excellent sensitivity and specificity (> 0.90) were achieved with both RADIAL and SI tools for NPC cases. The highest sensitivity was attained with the 2/7 SI, Refined SI and Top 3 RADIAL algorithms. Top 1 and Top 3 RADIAL were the most specific tools, followed by the Original SI. The individual comparison of each ARCA revealed that Wilson disease, PLA2G6-associated neurodegeneration, and hypomyelinating leukodystrophy (POLR3A) are frequent NPC false positives (PLA2G6 and POL3A only with the SIs). Both RADIAL and SI diagnostic approaches showed strong discriminatory potential and may be useful screening tools in different clinical contexts.
Collapse
Affiliation(s)
- Mathieu Anheim
- Department of Neurology, Hautepierre Hospital, University Hospital of Strasbourg, Strasbourg, France.
- Institute of Genetics and Molecular and Cellular Biology, INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch, France.
- Strasbourg Federation of Translational Medicine, University of Strasbourg, Strasbourg, France.
| | | | - Stefan A Kolb
- Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
37
|
MAEKAWA M, MANO N. Identification and Evaluation of Biomarkers for Niemann-Pick Disease Type C Based on Chemical Analysis Techniques. CHROMATOGRAPHY 2020. [DOI: 10.15583/jpchrom.2020.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
| | - Nariyasu MANO
- Department of Pharmaceutical Sciences, Tohoku University Hospital
| |
Collapse
|
|
38
|
Recent Advances in the Treatment of Cerebellar Disorders. Brain Sci 2019; 10:brainsci10010011. [PMID: 31878024 PMCID: PMC7017280 DOI: 10.3390/brainsci10010011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/13/2019] [Accepted: 12/20/2019] [Indexed: 12/19/2022] Open
Abstract
Various etiopathologies affect the cerebellum, resulting in the development of cerebellar ataxias (CAs), a heterogeneous group of disorders characterized clinically by movement incoordination, affective dysregulation, and cognitive dysmetria. Recent progress in clinical and basic research has opened the door of the ‘‘era of therapy” of CAs. The therapeutic rationale of cerebellar diseases takes into account the capacity of the cerebellum to compensate for pathology and restoration, which is collectively termed cerebellar reserve. In general, treatments of CAs are classified into two categories: cause-cure treatments, aimed at arresting disease progression, and neuromodulation therapies, aimed at potentiating cerebellar reserve. Both forms of therapies should be introduced as soon as possible, at a time where cerebellar reserve is still preserved. Clinical studies have established evidence-based cause-cure treatments for metabolic and immune-mediated CAs. Elaborate protocols of rehabilitation and non-invasive cerebellar stimulation facilitate cerebellar reserve, leading to recovery in the case of controllable pathologies (metabolic and immune-mediated CAs) and delay of disease progression in the case of uncontrollable pathologies (degenerative CAs). Furthermore, recent advances in molecular biology have encouraged the development of new forms of therapies: the molecular targeting therapy, which manipulates impaired RNA or proteins, and the neurotransplantation therapy, which delays cell degeneration and facilitates compensatory functions. The present review focuses on the therapeutic rationales of these recently developed therapeutic modalities, highlighting the underlying pathogenesis.
Collapse
|
|
39
|
Hastings C, Vieira C, Liu B, Bascon C, Gao C, Wang RY, Casey A, Hrynkow S. Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis. Orphanet J Rare Dis 2019; 14:228. [PMID: 31639011 PMCID: PMC6805667 DOI: 10.1186/s13023-019-1207-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/21/2019] [Indexed: 12/15/2022] Open
Abstract
Background Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Results Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. Conclusions These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.
Collapse
Affiliation(s)
- Caroline Hastings
- Department of Pediatric Hematology Oncology, UCSF Benioff Children's Hospital Oakland, 747 52nd Street, Oakland, CA, 94609-1809, USA. .,Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
| | - Camilo Vieira
- Universidade Federal da Bahia, Clínica Citta, Ed. Mundo Plaza, Av. Tancredo Neves, 620, Sala 1905, Camino dos Árvares, Salvador, Brazil
| | - Benny Liu
- GI & Liver Clinics, Highland Hospital, Alameda Health System, Highland Hospital, Oakland, CA, USA.,Division of Gastroenterology & Hepatology, Highland Hospital, Alameda Health Systems, Highland Care Pavilion 5th floor, 1411 East 31st Street, Oakland, CA, 94602, USA
| | - Cyrus Bascon
- Department of Pediatric Hematology Oncology, UCSF Benioff Children's Hospital Oakland, 747 52nd Street, Oakland, CA, 94609-1809, USA
| | - Claire Gao
- UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.,Present Address: Neuroscience Graduate Program, Brown University, 185 Meeting Street, Box GL-N, Providence, RI, 02912, USA
| | - Raymond Y Wang
- Division of Metabolic Disorders, Children's Hospital of Orange County, CHOC Children's Specialists, 1201 W. La Veta Ave, Orange, CA, 92868, USA.,Department of Pediatrics, University of California, Irvine School of Medicine, Irvine, CA, 92868, USA
| | - Alicia Casey
- Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Sharon Hrynkow
- CTD Holdings, Inc., P.O. Box 1180, Alachua, FL, 32616, USA
| |
Collapse
|
|
40
|
Bräuer AU, Kuhla A, Holzmann C, Wree A, Witt M. Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1. Int J Mol Sci 2019; 20:ijms20184392. [PMID: 31500175 PMCID: PMC6771135 DOI: 10.3390/ijms20184392] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann–Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.
Collapse
Affiliation(s)
- Anja U Bräuer
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany.
- Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany.
| | - Angela Kuhla
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany.
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
| | - Carsten Holzmann
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany.
| | - Andreas Wree
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany.
| | - Martin Witt
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany.
| |
Collapse
|
|
41
|
Giugliani L, Steiner CE, Kim CA, Lourenço CM, Santos MLSF, de Souza CFM, Brusius‐Facchin AC, Baldo G, Riegel M, Giugliani R. Clinical findings in Brazilian patients with adult GM1 gangliosidosis. JIMD Rep 2019; 49:96-106. [PMID: 31497487 PMCID: PMC6718113 DOI: 10.1002/jmd2.12067] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/12/2019] [Accepted: 06/24/2019] [Indexed: 11/20/2022] Open
Abstract
GM1 gangliosidosis is a lysosomal storage disorder caused by β-galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross-sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4-34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.
Collapse
Affiliation(s)
- Luciana Giugliani
- National Institute of Population Medical Genetics (INAGEMP)Porto AlegreBrazil
| | | | - Chong Ae Kim
- Instituto da CriançaHospital das Clínicas, FM, USPSão PauloBrazil
| | | | | | | | | | - Guilherme Baldo
- Gene Therapy Center, HCPAPorto AlegreBrazil
- Department of PhysiologyUFRGSPorto AlegreBrazil
- Post‐Graduate Program in PhysiologyUFRGSPorto AlegreBrazil
| | - Mariluce Riegel
- Medical Genetics Service, HCPAPorto AlegreBrazil
- Post‐Graduate Program in Genetics and Molecular BiologyUFRGSPorto AlegreBrazil
| | - Roberto Giugliani
- National Institute of Population Medical Genetics (INAGEMP)Porto AlegreBrazil
- Medical Genetics Service, HCPAPorto AlegreBrazil
- Post‐Graduate Program in Genetics and Molecular BiologyUFRGSPorto AlegreBrazil
- Department of GeneticsUFRGSPorto AlegreBrazil
| |
Collapse
|
|
42
|
Synofzik M, Puccio H, Mochel F, Schöls L. Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies. Neuron 2019; 101:560-583. [PMID: 30790538 DOI: 10.1016/j.neuron.2019.01.049] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 12/20/2018] [Accepted: 01/23/2019] [Indexed: 12/22/2022]
Abstract
Autosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade.
Collapse
Affiliation(s)
- Matthis Synofzik
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Hélène Puccio
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France; INSERM, U1258, 67404 Illkirch, France; CNRS, UMR7104, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France
| | - Fanny Mochel
- Sorbonne Université, UPMC-Paris 6, UMR S 1127 and Inserm U 1127, and CNRS UMR 7225, and Institut du Cerveau et de la Moelle épinière, 75013 Paris, France; Department of Genetics and Reference Centre for Adult Neurometabolic Diseases, AP-HP, La Pitié-Salpêtriere University Hospital, Paris, France
| | - Ludger Schöls
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
| |
Collapse
|
|
43
|
Jeong MS, Bae JS, Jin HK. Vascular endothelial growth factor improves the therapeutic effects of cyclodextrin in Niemann-Pick type C mice. Anim Cells Syst (Seoul) 2019; 23:346-354. [PMID: 31700700 PMCID: PMC6830204 DOI: 10.1080/19768354.2019.1651768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/17/2019] [Accepted: 07/25/2019] [Indexed: 11/04/2022] Open
Abstract
Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative disorder caused by a deficiency in the function of the NPC1 gene. Malfunction of this gene/protein leads to progressive accumulation of unesterified cholesterol and sphingolipids in many organs, including the brain. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive benefits. In this study, we have investigated the effects of combining centrally and systemically administered therapies in a mouse model of NP-C, i.e. overexpression of brain-specific vascular endothelial growth factor (VEGF) in combination with systemic administration of 2-hydroxypropyl-β-cyclodextrin (CD). We found that animals treated using a combination of VEGF and CD showed an improvement in pathophysiology compared to those treated with CD alone or brain VEGF overexpression alone, or non-treated NP-C mice. Combination therapy increased the time period over which NP-C mice maintained their body-weight and motor function, and decreased the abnormal accumulation of lipids. In addition, combination therapy delayed the onset of Purkinje cell loss and reduced neuroinflammation. Taken together, our results demonstrate that combination therapy using VEGF and CD is a promising therapeutic modality for treating NP-C, and suggest that it represents a potential strategy for the treatment of diseases that cause both visceral and brain pathologies.
Collapse
Affiliation(s)
- Min Seock Jeong
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, Korea.,Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Jae-Sung Bae
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, Korea.,Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea.,Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea
| | - Hee Kyung Jin
- KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, Korea.,Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| |
Collapse
|
|
44
|
Hammond N, Munkacsi AB, Sturley SL. The complexity of a monogenic neurodegenerative disease: More than two decades of therapeutic driven research into Niemann-Pick type C disease. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1109-1123. [PMID: 31002946 DOI: 10.1016/j.bbalip.2019.04.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/31/2019] [Accepted: 04/06/2019] [Indexed: 12/17/2022]
Abstract
Niemann-Pick type C (NP-C) disease is a rare and fatal neurodegenerative disease typified by aberrations in intracellular lipid transport. Cholesterol and other lipids accumulate in the late endosome/lysosome of all diseased cells thereby causing neuronal and visceral atrophy. A cure for NP-C remains elusive despite the extensive molecular advances emanating from the identification of the primary genetic defect in 1997. Penetration of the blood-brain barrier and efficacy in the viscera are prerequisites for effective therapy, however the rarity of NP-C disease is the major impediment to progress. Disease diagnosis is challenging and establishment of appropriate test populations for clinical trials difficult. Fortunately, disease models that span the diversity of microbial and metazoan life have been utilized to advance the quest for a therapy. The complexity of lipid storage in this disorder and in the model systems, has led to multiple theories on the primary disease mechanism and consequently numerous and varied proposed interventions. Here, we conduct an evaluation of these studies.
Collapse
Affiliation(s)
- Natalie Hammond
- School of Biological Sciences, Victoria University of Wellington, Wellington 6012, New Zealand
| | - Andrew B Munkacsi
- School of Biological Sciences, Victoria University of Wellington, Wellington 6012, New Zealand.
| | - Stephen L Sturley
- Department of Biology, Barnard College-Columbia University, New York, NY 10027, United States of America.
| |
Collapse
|
|
45
|
Bonnot O, Gama CS, Mengel E, Pineda M, Vanier MT, Watson L, Watissée M, Schwierin B, Patterson MC. Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry. World J Biol Psychiatry 2019; 20:310-319. [PMID: 28914127 DOI: 10.1080/15622975.2017.1379610] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Results: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.
Collapse
Affiliation(s)
- Olivier Bonnot
- a Department of Child and Adolescent Psychiatry , University and CHU of Nantes , Nantes , France
| | - Clarissa S Gama
- b Laboratory of Molecular Psychiatry , Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul , Porto Alegre , Brazil
| | - Eugen Mengel
- c Paediatric and Adolescent Medical Centre , Johannes Gutenberg University , Mainz , Germany
| | - Mercè Pineda
- d Department of Neuropediatrica , Fundacio Hospital Sant Joan de Déu , Barcelona , Spain
| | - Marie T Vanier
- e Metabolomic and Metabolic Diseases , INSERM Unit 820 , Lyon , France
| | | | - Marie Watissée
- g Actelion Pharmaceuticals Ltd , Allschwil , Switzerland
| | | | - Marc C Patterson
- h Pediatric and Adolescent Medicine , Mayo Clinic , Rochester , MN , USA
| |
Collapse
|
|
46
|
Bonnot O, Klünemann HH, Velten C, Torres Martin JV, Walterfang M. Systematic review of psychiatric signs in Niemann-Pick disease type C. World J Biol Psychiatry 2019; 20:320-332. [PMID: 29457916 DOI: 10.1080/15622975.2018.1441548] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Objectives: We conducted the first systematic literature review and analysis of psychiatric manifestations in Niemann-Pick disease type C (NPC) to describe: (1) time of occurrence of psychiatric manifestations relative to other disease manifestations; and (2) frequent combinations of psychiatric, neurological and visceral disease manifestations. Methods: A systematic EMBase literature search was conducted to identify, collate and analyze published data from patients with NPC associated with psychiatric symptoms, published between January 1967 and November 2015. Results: Of 152 identified publications 40 were included after screening that contained useable data from 58 NPC patients (mean [SD] age at diagnosis of NPC 27.8 [15.1] years). Among patients with available data, cognitive, memory and instrumental impairments were most frequent (90% of patients), followed by psychosis (62%), altered behavior (52%) and mood disorders (38%). Psychiatric manifestations were reported before or at neurological disease onset in 41 (76%) patients; organic signs (e.g., hepatosplenomegaly, hearing problems) were reported before psychiatric manifestations in 12 (22%). Substantial delays to diagnosis were observed (5-6 years between psychiatric presentation and NPC diagnosis). Conclusions: NPC should be considered as a possible cause of psychiatric manifestations in patients with an atypical disease course, acute-onset psychosis, treatment failure, and/or certain combinations of psychiatric/neurological/visceral symptoms.
Collapse
Affiliation(s)
- Olivier Bonnot
- a Child and Adolescent Psychiatry Department , CHU and University of Nantes , Nantes , France
| | - Hans-Hermann Klünemann
- b University Clinic for Psychiatry and Psychotherapy, Regensburg University , Regensburg , Germany
| | | | | | | |
Collapse
|
|
47
|
Santiago-Mujica E, Flunkert S, Rabl R, Neddens J, Loeffler T, Hutter-Paier B. Hepatic and neuronal phenotype of NPC1 -/- mice. Heliyon 2019; 5:e01293. [PMID: 30923761 PMCID: PMC6423819 DOI: 10.1016/j.heliyon.2019.e01293] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 01/15/2019] [Accepted: 02/26/2019] [Indexed: 12/14/2022] Open
Abstract
Niemann-Pick type C disease (NPC) is a fatal autosomal recessive disorder characterized by a defect in the intracellular transport of lipoproteins leading to the accumulation of lipids in diverse tissues. A visceral and neuronal phenotype mimicking human NPC1 disease has been described in NPC1 mutant mice. These mice are by now the most widely used NPC1 rodent model to study NPC and developmental compounds against this devastating disease. Here we characterized NPC1-/- mice for their hepatic and neuronal phenotype to confirm the stability of the phenotype, provide a characterization of disease progression and pinpoint the age of robust phenotype onset. Animals of 4-10 weeks of age were analyzed for general health, motor deficits as well as hepatic and neuronal alterations with a special focus on cerebellar pathology. Our results show that NPC1-/- mice have a reduced general health at the age of 9-10 weeks. Robust motor deficits can be observed even earlier at 8 weeks of age. Hepatic changes included increased organ weight and cholesterol levels at 6 weeks of age accompanied by severely increased liver enzyme levels. Analysis of NPC1-/- brain pathology showed decreased cholesterol and increased Aβ levels in the hippocampus at the age of 6 weeks. Further analysis revealed a decrease of the cytokine IL-12p70 in the cerebellum along with a very early increase of astrocytosis. Hippocampal IL-12p70 levels were increased at the age of 6 weeks followed by increased activated microglia levels. By the age of 10 weeks, also cerebellar Aβ levels were increased along with strongly reduced Calbindin D-28k levels. Our results validate and summarize the progressive development of the hepatic and neuronal phenotype of NPC1-/- mice that starts with cerebellar astrocytosis, making this mouse model a valuable tool for the development of new compounds against NPC.
Collapse
Key Words
- AAALAC, Association for Assessment and Accreditation of Laboratory Animal Care
- ALT, alanine aminotransferase
- ANOVA, Analysis of variance
- AOI, Area of interest
- AP, alkaline phosphatase
- APP, Amyloid Precursor Protein
- AST, aspartate aminotransferase
- CD45, cluster of differentiation 45
- CNS, central nervous system
- Cell biology
- DAPI, 4′,6-Diamidin-2-phenylindol
- GFAP, Glial fibrillary acidic protein
- IFN-γ, Interferon-gamma
- IL-10/12, Interleukin-10/12
- KC, keratinocyte chemoattractant
- MAP2, microtubuli-associated protein 2
- Molecular biology
- NPC, Niemann-Pick type C
- Neuroscience
- Physiology
- TNF-α, tumor necrosis factor-alpha
- WT, wildtype
Collapse
|
|
48
|
de Silva R, Greenfield J, Cook A, Bonney H, Vallortigara J, Hunt B, Giunti P. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis 2019; 14:51. [PMID: 30786918 PMCID: PMC6381619 DOI: 10.1186/s13023-019-1013-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 01/29/2019] [Indexed: 11/26/2022] Open
Abstract
The progressive ataxias are a group of rare and complicated neurological disorders, knowledge of which is often poor among healthcare professionals (HCPs). The patient support group Ataxia UK, recognising the lack of awareness of this group of conditions, has developed medical guidelines for the diagnosis and management of ataxia. Although ataxia can be a symptom of many common conditions, the focus here is on the progressive ataxias, and include hereditary ataxia (e.g. spinocerebellar ataxia (SCA), Friedreich’s ataxia (FRDA)), idiopathic sporadic cerebellar ataxia, and specific neurodegenerative disorders in which ataxia is the dominant symptom (e.g. cerebellar variant of multiple systems atrophy (MSA-C)). Over 100 different disorders can lead to ataxia, so diagnosis can be challenging. Although there are no disease-modifying treatments for most of these entities, many aspects of the conditions are treatable, and their identification by HCPs is vital. The early diagnosis and management of the (currently) few reversible causes are also of paramount importance. More than 30 UK health professionals with experience in the field contributed to the guidelines, their input reflecting their respective clinical expertise in various aspects of ataxia diagnosis and management. They reviewed the published literature in their fields, and provided summaries on “best” practice, including the grading of evidence available for interventions, using the Guideline International Network (GIN) criteria, in the relevant sections. A Guideline Development Group, consisting of ataxia specialist neurologists and representatives of Ataxia UK (including patients and carers), reviewed all sections, produced recommendations with levels of evidence, and discussed modifications (where necessary) with contributors until consensus was reached. Where no specific published data existed, recommendations were based on data related to similar conditions (e.g. multiple sclerosis) and/or expert opinion. The guidelines aim to assist HCPs when caring for patients with progressive ataxia, indicate evidence-based (where it exists) and best practice, and act overall as a useful resource for clinicians involved in managing ataxic patients. They do, however, also highlight the urgent need to develop effective disease-modifying treatments, and, given the large number of recommendations based on “good practice points”, emphasise the need for further research to provide evidence for effective symptomatic therapies. These guidelines are aimed predominantly at HCPs in secondary care (such as general neurologists, clinical geneticists, physiotherapists, speech and language therapists, occupational therapists, etc.) who provide care for individuals with progressive ataxia and their families, and not ataxia specialists. It is a useful, practical tool to forward to HCPs at the time referrals are made for on-going care, for example in the community.
Collapse
Affiliation(s)
- Rajith de Silva
- Department of Neurology, Essex Centre for Neurological Sciences, Queen's Hospital, Romford, RM7 0AG, UK
| | | | - Arron Cook
- Ataxia Centre, Department of Molecular Neurosciences, UCL Queen Sqaure Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | | | | | - Barry Hunt
- Ataxia UK, 12 Broadbent Close, London, N6 5JW, UK
| | - Paola Giunti
- Ataxia Centre, Department of Molecular Neurosciences, UCL Queen Sqaure Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
| |
Collapse
|
|
49
|
Psychiatric and Cognitive Symptoms Associated with Niemann-Pick Type C Disease: Neurobiology and Management. CNS Drugs 2019; 33:125-142. [PMID: 30632019 DOI: 10.1007/s40263-018-0599-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.
Collapse
|
|
50
|
Genetic mimics of the non-genetic atypical parkinsonian disorders – the ‘atypical’ atypical. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 149:327-351. [DOI: 10.1016/bs.irn.2019.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|