Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Hum Mol Genet ; 30(24): 2456-2468, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34296265

RESUMO

The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-ß-cyclodextrin (HPßCD), a compound currently under investigation in clinical trials. A total of 485 HPßCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of plasma from Npc1m1N null mice treated with HPßCD and adeno-associated virus gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPßCD treatment.


Assuntos
Doença de Niemann-Pick Tipo C , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Biomarcadores , Modelos Animais de Doenças , Proteínas do Olho/genética , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia , Transcriptoma
2.
Methods Cell Biol ; 126: 331-47, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25665453

RESUMO

Biomarkers are important tools in medicine, which can be used for monitoring disease progression and response to therapy. One of the main problems in rare lysosomal storage diseases is that there are over 70 different diseases, all with different biochemical storage profiles. Developing biochemical biomarkers therefore requires an individual assay per disease/subgroup of diseases. An alternative approach is to develop an assay that is independent of the specific macromolecules stored. This chapter discusses an assay that may serve as a universal biomarker for these diseases and measures the expansion of the late endosomal/lysosomal system. We have developed an assay that takes advantage of a commercially available late endosomal/lysosomal probe, LysoTracker, which becomes trapped in the acidic compartment of cells and emits a fluorescent signal that can be detected using flow cytometry. In this chapter, we detail the methodology behind this assay and discuss the factors that need to be considered when establishing this assay in clinical and research settings.


Assuntos
Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/patologia , Animais , Antígenos CD19/metabolismo , Linfócitos B/patologia , Humanos , Tamanho das Organelas
3.
J Clin Invest ; 124(3): 1320-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24487591

RESUMO

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


Assuntos
Linfócitos B/patologia , Lisossomos/patologia , Doença de Niemann-Pick Tipo C/patologia , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Biomarcadores , Transplante de Medula Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/terapia , Estudos Prospectivos , Proteínas/genética , Índice de Gravidade de Doença , Resultado do Tratamento , beta-Ciclodextrinas/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...