A5056749721- Lysosomal Storage Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Meteorological Phenomena and Simulations
- Neurogenetic and Muscular Disorders Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Neurogenesis and neuroplasticity mechanisms
- Cytomegalovirus and herpesvirus research
- Sphingolipid Metabolism and Signaling
- Cellular transport and secretion
- Autoimmune and Inflammatory Disorders Research
- Precipitation Measurement and Analysis
- Geophysics and Gravity Measurements
- Climate variability and models
- Neuroendocrine regulation and behavior
- Circadian rhythm and melatonin
- Hypothalamic control of reproductive hormones
- Tropical and Extratropical Cyclones Research
- Solar and Space Plasma Dynamics
- Virus-based gene therapy research
- Lipid Membrane Structure and Behavior
- Atmospheric and Environmental Gas Dynamics
- Atmospheric aerosols and clouds
- Glycosylation and Glycoproteins Research
- RNA Interference and Gene Delivery
Sanofi (United States)
2016-2024
AVEO Oncology (United States)
2023
Sanofi (Mexico)
2021-2023
Framingham State University
2021
American Institute of Aeronautics and Astronautics
2008
Stinger Ghaffarian Technologies (United States)
2008
Goddard Space Flight Center
2008
Honeywell (United States)
2008
SynZyme Technologies (United States)
2007
Icahn School of Medicine at Mount Sinai
2005
Mutations of GBA1 , the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients or without mutations also exhibit lower enzymatic levels glucocerebrosidase in central nervous system (CNS), suggesting possible link between enzyme development disease. Previously, we have shown that early treatment can modulate α-synuclein aggregation presymptomatic mouse model Gaucher-related...
Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found affected brain regions, but how iron accumulation influences physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived grown a tri-culture system highly responsive susceptible ferroptosis, an iron-dependent form of cell death. Furthermore, overload causes marked...
Significance Mutations in the glucocerebrosidase gene ( GBA ) represent most common genetic risk factor for Parkinson’s disease (PD), affecting 5–10% of patients and accelerating progression. consequent loss enzymatic activity allow glucocerebrosides to build up cells. Here, we tested an experimental drug that inhibits production glucocerebrosides, hypothesizing producing fewer lipids may counteract challenge clearing them from In mice with mutant Gba , prolonged administration this...
Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal protease tripeptidyl peptidase 1 (TPP1). LINCL characterized clinically progressive motor and cognitive decline, premature death. Enzyme-replacement therapy (ERT) currently available for storage diseases affecting peripheral tissues, but has not been used patients with central nervous system (CNS) involvement. Enzyme delivery...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models ALS has shown that insulin-like growth factor-1 (IGF-1) slows progression when delivered at onset. However, IGF-1's mechanism action along neuromuscular axis remains unclear. In this study, symptomatic mice received IGF-1 through stereotaxic injection an IGF-1-expressing viral vector to deep cerebellar nuclei (DCN), region cerebellum with extensive brain stem and spinal...
Significance Glycosphingolipids are a heterogeneous group of membrane lipids formed through the covalent linkage glycan moiety to ceramide. Genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases. Here, we investigated whether alterations glycosphingolipids contribute neurodegeneration amyotrophic lateral sclerosis (ALS). We show ALS patients and model mice display disease-related changes spinal cord levels enzymes...
Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation Cu/Zn superoxide dismutase 1 gene) ALS enters progressive state acidosis associated with several metabolic (hormonal) alternations favor lipolysis. Extensive investigation major determinants H + concentration (i.e., strong ion difference and gap) suggests also due part to presence unknown anion....
Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a lysosomal storage disorder caused by mutations in CLN2 , which encodes tripeptidyl peptidase I (TPP1). Lack of TPP1 results accumulation autofluorescent material and curvilinear bodies cells throughout the CNS, leading to progressive neurodegeneration death typically childhood. In this study, we injected adeno-associated virus (AAV) vectors containing human cDNA into brains −/− mice determine therapeutic efficacy. AAV2 CU...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron cell death in the cortex, brainstem, and spinal cord. Extensive efforts have been made to develop trophic factor-based therapies enhance survival; however, achievement of adequate therapeutic delivery all regions corticospinal tract has remained significant challenge. Here, we show that adeno-associated virus serotype 4 (AAV4)-mediated expression insulin-like growth factor-1 (IGF-1) or...
Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results cellular accumulation sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated potential AAV-mediated expression to correct brain pathology an knockout (ASMKO) mouse model NPA. An AAV serotype 2 vector encoding human (AAV2-hASM) was injected directly into adult ASMKO hippocampus...
Pompe disease (glycogen storage II) is caused by mutations in the acid α-glucosidase gene. The most common form rapidly progressive with glycogen storage, particularly muscle, which leads to profound weakness, cardiac failure, and death age of 2 years. Although usually considered a muscle disease, also occurs CNS. We evaluated progression neuropathologic behavioral abnormalities mouse model (6neo/6neo) that displays many features human disease. Homozygous mutant mice store excess within...
Spinal muscular atrophy is a progressive motor neuron disease caused by deficiency of survival neuron. In this study, we evaluated the efficacy intravenous administration recombinant adeno-associated virus (AAV1) vector encoding human insulin-like growth factor-1 (IGF-1) in severe mouse model spinal atrophy. Measurable quantities IGF-1 transcripts and protein were detected liver (up to 3 months postinjection) serum indicating that was secreted from into systemic circulation. mice...
Mutations in GBA1, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson's disease (PD) and dementia Lewy bodies. A higher prevalence increased severity motor non-motor symptoms is observed PD patients harboring mutant GBA1 alleles, suggesting a link between or product development. Interestingly, without mutations also exhibit lower levels glucocerebrosidase activity central nervous system (CNS), implicating this...
Promoting myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a promising therapeutic approach for CNS demyelinating disorders such as Multiple Sclerosis (MS). To aid in the discovery myelination-promoting compounds, we generated genome-engineered human pluripotent stem cell (hPSC) line that consists three reporters: identification-and-purification tag, GFP, and secreted-NanoLuc, driven by PDGFRA, PLP1, MBP genes, respectively. Using this line, established...
Niemann-Pick type A disease is a lysosomal storage disorder caused by deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that pathology the ASM knockout (ASMKO) mouse brain can be corrected adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared relative therapeutic efficacy of different recombinant AAV vectors (1, 2, 5, 7, and 8) using histological, biochemical, behavioral endpoints. In addition, evaluated use deep cerebellar...
Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol lysosomes. In present study, we evaluated effects direct intracerebral transplantation neural progenitor cells (NPCs) on brain storage pathology ASM knock-out (ASMKO) mouse model Type A disease. NPCs derived from adult were genetically modified express human (hASM) transplanted into multiple regions ASMKO brain. Transplanted...
Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as result mutations in CLN2. Absence TPP1 results lysosomal storage with an accompanying axonal degeneration throughout central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared efficacies pre- post-symptomatic injections recombinant adeno-associated virus (AAV) for treating cellular...
Niemann-Pick disease (NPD) is caused by the loss of acid sphingomyelinase (ASM) activity, which results in widespread accumulation undegraded lipids cells viscera and CNS. In this study, we tested effect combination brain systemic injections recombinant adeno-associated viral vectors encoding human ASM (hASM) a mouse model NPD. Animals treated therapy exhibited high levels hASM brain, resulted near-complete correction storage throughout body. This global reversal pathology translated to...
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it unclear whether lipid homeostasis adversely affected in the spinal cord gray matter (GM), and if so, because of an aberrant increase synthesis. Moreover, unknown contributes to MN Here, we show that cholesterol ester (CE) triacylglycerol levels are elevated several-fold GM male sporadic ALS patients. Interestingly, HMG-CoA...
Abstract Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that due to motor neuron (MN) death. Cellular toxicity from excess averted when it enzymatically oxidized oxysterols and bile acids (BAs) promote its removal. In contrast, auto oxidation often detrimental cellular survival. Although metabolites are altered blood CSF ALS patients, unknown if increased occurs SC during ALS, exposure affects human MN...
Abstract Precipitation is an important environmental parameter but also one which very inadequately measured and monitored across the surface of Earth. In recent years increasing attention has been paid to use satellites for improved rainfall measurement monitoring, interest grown in projects aimed at intercomparing where possible "validating" different satellite evaluation algorithms. This paper introduces first (algorithm) Intercomparison Project (PIP‐1) organized by Working Group NASA‐led...