Elliot R. Thomsen
A5080943106- Neuroinflammation and Neurodegeneration Mechanisms
- Alzheimer's disease research and treatments
- Single-cell and spatial transcriptomics
- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Neural dynamics and brain function
- Trypanosoma species research and implications
- Cell Image Analysis Techniques
- Bioinformatics and Genomic Networks
- Monoclonal and Polyclonal Antibodies Research
- Glycogen Storage Diseases and Myoclonus
- Neuroscience and Neuropharmacology Research
- Peroxisome Proliferator-Activated Receptors
- Hepatitis C virus research
- Nuclear Receptors and Signaling
- Neurogenesis and neuroplasticity mechanisms
- Gene expression and cancer classification
- Gene Regulatory Network Analysis
- Inflammation biomarkers and pathways
- Cerebrospinal fluid and hydrocephalus
- Neonatal and fetal brain pathology
- Photoreceptor and optogenetics research
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Enzyme Production and Characterization
Denali Therapeutics (United States)
2020-2024
Allen Institute
2015-2023
Allen Institute for Brain Science
2015-2023
Prognosys Biosciences (United States)
2012-2013
Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced...
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...
Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these cell-specific properties not been well investigated in human cortex, where there major technical challenges reliably obtaining healthy tissue, conducting multiple patch-clamp recordings types, and identifying those types. Here, we take advantage of newly developed methods for neurosurgical tissue analysis with recordings,
Background There is a growing appreciation of the role proteolytic processes in human health and disease, but tools for analysis such on proteome-wide scale are limited. Furin ubiquitous proprotein convertase that cleaves after basic residues transforms secretory proproteins into biologically active proteins. Despite this important role, many furin substrates remain unknown proteome. Methodology/Principal Findings We devised an approach proteinase target identification combines silico...
Abstract Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem this class drugs. Here, we report an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) brain delivery amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in mouse model deposition. Asymmetrical Fc mutations (ATV cisLALA )...
The hepatitis C virus (HCV) genome encodes a long polyprotein, which is processed by host cell and viral proteases to the individual structural non-structural (NS) proteins. HCV NS3/4A serine proteinase (NS3/4A) non-covalent heterodimer of N-terminal, ∼180-residue portion 631-residue NS3 protein with NS4A co-factor. cleaves polyprotein sequence at four specific regions. essential for replication has been considered an attractive drug target.
Abstract Elucidating the cellular architecture of human neocortex is central to understanding our cognitive abilities and susceptibility disease. Here we applied single nucleus RNA-sequencing perform a comprehensive analysis cell types in middle temporal gyrus cerebral cortex. We identify highly diverse set excitatory inhibitory neuronal that are mostly sparse, with being less layer-restricted than expected. Comparison similar mouse cortex dataset revealed surprisingly well-conserved enables...
Abstract Defining a complete set of cell types within the cortex requires reconciling disparate results achieved through diverging methodologies. To address this correspondence problem, multiple methodologies must be applied to same cells across single-cell experiments. Here we present new approach applying spatial transcriptomics using multiplexed fluorescence in situ hybridization, (mFISH) brain tissue previously interrogated two photon optogenetic mapping synaptic connectivity. This can...
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation glycosaminoglycans (GAGs) throughout body. Treatment MPS remains considerable challenge as current enzyme replacement therapies do not adequately control many aspects disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that engineered to bind transferrin receptor; this...
We report a scalable and cost-effective technology for generating screening high-complexity customizable peptide sets. The peptides are made as peptide-cDNA fusions by in vitro transcription/translation from pools of DNA templates generated microarray-based synthesis. This approach enables large custom sets to be designed silico, manufactured cost-effectively parallel, assayed efficiently multiplexed fashion. utility our fusion was demonstrated two activity-based assays discover protease...
We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability reduce glycosaminoglycan (GAG) accumulation in brains of mouse model mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) simultaneously measure heparan sulfate dermatan derived...
ABSTRACT Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these cell-specific properties not been well investigated in human cortex, where there major technical challenges reliably identifying types. Here, we take advantage of newly developed methods for neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent situ hybridization (FISH), and prospective...
Abstract Microglial dysfunction is believed to play a pathogenic role in Alzheimer’s disease (AD). Here, we characterize the amyloid-β related pathology and microglial responses an engineered APP knock-in mouse model of familial AD. This recapitulates key pathological features AD such as progressive accumulation parenchymal amyloid plaques vascular deposits, altered glial neurodegeneration. Leveraging multi-omics approaches, found lipid exacerbated disease-associated transcriptomic response...
Abstract Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...