Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1

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.

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Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

Disease Models & Mechanisms ◽

10.1242/dmm.012385 ◽

2013 ◽

Vol 6 (5) ◽

pp. 1089-1100 ◽

Cited By ~ 15

Author(s):

M. E. Lopez ◽

M. P. Scott

Keyword(s):

Mouse Models ◽

Neurodegenerative Disorder ◽

Disease Type ◽

Lessons Learned ◽

Genetic Dissection ◽

Niemann Pick Disease ◽

A Cell ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Modelling Niemann-Pick disease type C in a human haploid cell line allows for patient variant characterization and clinical interpretation

10.1101/801019 ◽

2019 ◽

Author(s):

Steven Erwood ◽

Reid A. Brewer ◽

Teija M.I. Bily ◽

Eleonora Maino ◽

Liangchi Zhou ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Cell Model ◽

Disease Type ◽

Haploid Cell ◽

Clinical Interpretation ◽

Base Editing ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Pick Disease

AbstractThe accurate clinical interpretation of human sequence variation is foundational to personalized medicine. This remains a pressing challenge, however, as genome sequencing becomes routine and new functionally undefined variants rapidly accumulate. Here, we describe a platform for the rapid generation, characterization and interpretation of genomic variants in haploid cells focusing on Niemann-Pick disease type C (NPC) as an example. NPC is a fatal neurodegenerative disorder characterized by a lysosomal accumulation of unesterified cholesterol and glycolipids. In 95% of cases, NPC is caused by mutations in the NPC1 gene, where over 200 unique disease-causing variants have been reported to date. Furthermore, the majority of patients with NPC are compound heterozygotes that often carry at least one private mutation, presenting a challenge for the characterization and classification of individual variants. Here, we have developed the first haploid cell model of NPC. This haploid cell model recapitulates the primary biochemical and molecular phenotypes typically found in patient-derived fibroblasts, illustrating its utility in modelling NPC. Additionally, we demonstrate the power of CRISPR-Cas9-mediated base editing in quickly and efficiently generating haploid cell models of individual patient variants in NPC. These models provide a platform for understanding the disease mechanisms underlying individual NPC1 variants while allowing for definitive clinical variant interpretation for NPC. While this study has focused on modelling NPC, the outlined approach could be translated widely and applied to a variety of genetic disorders or understanding the pathogenicity of somatic mutations in cancer.

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Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child

Case Reports in Pediatrics ◽

10.1155/2015/807591 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Ryo Suzuki ◽

Atsushi Tanaka ◽

Toshiharu Matsui ◽

Tetsuki Gunji ◽

Jun Tohyama ◽

...

Keyword(s):

Developmental Coordination Disorder ◽

Neurodegenerative Disorder ◽

Neurodevelopmental Disorder ◽

Disease Type ◽

Childhood Development ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Coordination Disorder ◽

Pick Disease

Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative disorder, often with onset after normal early childhood development. Juvenile onset NPC patients slowly develop cerebellar symptoms and cognitive impairment and often experience difficulties at school. However, these problems may be overlooked due to the unpublicized nature of NPC, given that it is a rare metabolic disorder. In this report, we present an 11-year-old male NPC patient, who suffered from clumsiness and difficulties in attention and academic and social skills. His symptoms were initially considered to be due to developmental coordination disorder (DCD) coexisting with bullying by peers. DCD is a type of neurodevelopmental disorder defined according to DSM-IV and is characterized by clumsiness that interferes with academic achievement and social integration not due to other general medical conditions. However, a detailed investigation of the patient suggested that the problems could be attributed to the onset of NPC. Clinicians should keep neurodegenerative disorders as differential diagnosis of children with multiple school problems.

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Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs

PLoS ONE ◽

10.1371/journal.pone.0243746 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243746

Author(s):

Ryuta Shioi ◽

Fumika Karaki ◽

Hiromasa Yoshioka ◽

Tomomi Noguchi-Yachide ◽

Minoru Ishikawa ◽

...

Keyword(s):

Kinase Inhibitor ◽

Neurodegenerative Disorder ◽

Drug Repurposing ◽

Disease Type ◽

Loss Of Function ◽

Pharmacological Chaperones ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Pick Disease

Niemann-Pick disease type C is a rare, fatal neurodegenerative disorder characterized by massive intracellular accumulation of cholesterol. In most cases, loss-of-function mutations in the NPC1 gene that encodes lysosomal cholesterol transporter NPC1 are responsible for the disease, and more than half of the mutations are considered to interfere with the biogenesis or folding of the protein. We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones. A photo-crosslinking study confirmed direct binding of itraconazole to a representative folding-defective mutant protein, NPC1-I1061T. Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the oxysterol-derived chaperones or an HDAC inhibitor, LBH-589, our findings should offer new starting points for medicinal chemistry efforts to develop better pharmacological chaperones for NPC1.

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