A5026435689- Lysosomal Storage Disorders Research
- Cytomegalovirus and herpesvirus research
- Autoimmune and Inflammatory Disorders Research
- Child Nutrition and Feeding Issues
- Glycogen Storage Diseases and Myoclonus
- Carbohydrate Chemistry and Synthesis
- Neonatal and fetal brain pathology
- Sphingolipid Metabolism and Signaling
- Calcium signaling and nucleotide metabolism
- Cellular transport and secretion
- Cerebral Palsy and Movement Disorders
- Neurogenetic and Muscular Disorders Research
- Adenosine and Purinergic Signaling
- Autophagy in Disease and Therapy
- HIV-related health complications and treatments
- Parkinson's Disease Mechanisms and Treatments
- Trypanosoma species research and implications
- Hemoglobinopathies and Related Disorders
- Pancreatic function and diabetes
- Alzheimer's disease research and treatments
- Mosquito-borne diseases and control
- Erythrocyte Function and Pathophysiology
- Metabolism and Genetic Disorders
- Genetics and Neurodevelopmental Disorders
- PARP inhibition in cancer therapy
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2024-2025
National Institutes of Health
2019-2025
National Human Genome Research Institute
2019-2024
Albert Einstein College of Medicine
2010-2019
John F. Kennedy Center for the Performing Arts
2009-2019
Bergen Kommune
2012
Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by defect in the NPC1 protein and characterized widespread intracellular accumulation of unesterified cholesterol glycosphingolipids (GSLs). While current treatment therapies are limited, few drugs tested Npc1(-/-) mice have shown partial benefit. During combination trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) allopregnanolone, we noted increased lifespan for receiving only...
Intracisternal injection of cyclodextrin into cats with Niemann-Pick type C1 disease results in Purkinje cell survival and normal neurological function, suggesting its usefulness for treating the human disease.
Niemann-Pick disease type C (NPC) and Wolman are two members of a family storage disorders caused by mutations genes encoding lysosomal proteins. Deficiency in function either the NPC1 or NPC2 protein NPC acid lipase results defective cellular cholesterol trafficking. Lysosomal accumulation enlarged lysosomes shared phenotypic characteristics both cells. Utilizing screen an approved drug collection, we found that δ-tocopherol effectively reduced accumulation, decreased volume, increased...
Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol–sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1 I1061T , encodes misfolded protein with reduced half-life caused ER-associated degradation. Therapies directed at stabilization of the mutant reduce cholesterol in fibroblasts but have not been tested vivo because lack suitable animal model. Whereas...
Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus requirements of NPC1 in vitro, its roles replication and pathogenesis vivo remain unclear. Here, we evaluated importance NPC1, partner cholesterol transport, NPC2, by using a mouse model Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads succumbed to EBOV infection, Npc1(-/-) were entirely free...
Niemann-Pick type C (NPC)1 is a rare neurodegenerative disease for which treatment options are limited. A major barrier to development of effective treatments has been the lack validated biomarkers monitor progression or serve as outcome measures in clinical trials. Using targeted metabolomics exploit complex lipid storage phenotype that hallmark NPC1 disease, we broadly surveyed Npc1(-/-) mouse tissues and identified elevated species across multiple sphingolipid classes increased with...
Mutations in solute carrier family 9 isoform 6 on chromosome Xq26.3 encoding sodium-hydrogen exchanger 6, a protein mainly expressed early and recycling endosomes are known to cause complex slowly progressive degenerative human neurological disease. Three resulting phenotypes have so far been reported: an X-linked Angelman syndrome-like condition, Christianson syndrome corticobasal degeneration with tau deposition, each characterized by severe intellectual disability, epilepsy, autistic...
Niemann–Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation cholesterol glycosphingolipids in late endosomes early lysosomes. In order identify pathological mechanisms underlying NPC uncover potential biomarkers, we gene expression changes an Npc1 mouse model at six ages spanning progression disease. We identified altered all ages, including asymptomatic, 1-week-old...
Objective Niemann–Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism action remains unresolved, administration 2-hydroxypropyl-β-cyclodextrin (HPβCD) has provided the greatest amelioration in animal models but ototoxic. We evaluated cyclodextrins (CDs) for treatment outcome chemical interaction with disease-relevant substrates that could pertain...
Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 (Npc1-/-) displays rapidly progressing form which weight loss, ataxia, increased cholesterol storage, loss cerebellar Purkinje neurons early lethality. To test the potential efficacy gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver under...
Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variations in NPC1. We and others have previously demonstrated the efficacy of systemic adeno-associated virus (AAV) gene therapy with AAV9 murine models The presence neutralizing antibodies (NAbs) natural exposure to wildtype AAVs may impair AAV transduction reduce or negate benefit therapy. In addition, there remains question whether individuals seroconvert age seroconversion limits...
ABSTRACT Identifying meaningful predictors of therapeutic efficacy from preclinical studies is challenging. However, clinical manifestations occurring in both patients and mammalian models offer significant translational value. Many neurological disorders, including inherited, metabolic Niemann–Pick disease, type C (NPC), exhibit ataxia. Both individuals with NPC murine manifest ataxia, investigational therapies impacting this phenotype mice have been reported to slow disease progression...
2-hydroxypropyl-β-cyclodextrin (CYCLO), a modifier of cholesterol efflux from cellular membrane and endo-lysosomal compartments, reduces lysosomal lipid accumulations has therapeutic effects in animal models Niemann-Pick disease type C several other neurodegenerative states. Here, we investigated CYCLO on autophagy wild-type mice TgCRND8 mice-an Alzheimer's Disease (AD) model exhibiting β-amyloidosis, neuronal deficits leading to protein accumulation within greatly enlarged autolysosomes. A...
Lysosomal diseases are a family of over 50 disorders caused by defects in proteins critical for normal function the endosomal/lysosomal system and characterized complex pathogenic cascades involving progressive dysfunction many organ systems, most notably brain. Evidence suggests that compromise lysosomal is highly varied leads to changes multiple substrate processing endosomal signalling, calcium homoeostasis endoplasmic reticulum stress, autophagocytosis proteasome function. Neurons...
Niemann-Pick disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As result, there accumulation of unesterified cholesterol and sphingolipids late endosomal/lysosomal system. This abnormal results cascade pathophysiological events including progressive, cerebellar neurodegeneration, among others. While significant progress has been made to better understand NPC1, downstream effects storage major mechanisms that drive...
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 hepatosplenomegaly, neurological degeneration premature death. timing severity NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data 42 patient-derived, primary fibroblast cell lines determine transcriptional changes induced by treatment with...
Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative caused by mutations in NPC1 , which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves accumulation of and lipids, leading to neurological visceral complications. Targeting central nervous system (CNS) from systemic circulation complicates treatment diseases with gene transfer techniques. Selected engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS...