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Comprehensive Botulinum Characterization via the Bilayer Nanowell Integrated Assay

通过双层纳米井综合测定进行全面的肉毒杆菌表征

基本信息

批准号：
10480376
负责人：
Eric Ervin
金额：
$ 40万
依托单位：
ELECTRONIC BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480376
关键词：
Acetylcholine Animals Anorexia Anxiety Area Binding Biological Assay Biological Response Modifier Therapy Biological Sciences Bontoxilysin Botox Botulinum Toxins Breathing Cell Wall Cell membrane Cell physiology Cells Cessation of life Cholera Clinical Complex Cosmetics Cytosol Development Devices Diphtheria Disease Dose Electrodes Endocytosis Endpoint Determination Ensure Enzymes Etiology Evaluation Face Fatigue Fluorescence Focal Dystonias Formulation Future Gold Growth Guidelines Health Healthcare Hour Human In Vitro Individual Integral Membrane Protein Intoxication Intraperitoneal Injections Ions Lead Lethal Dose 50 Light Lipid Bilayers Manufacturer Name Measurement Measures Mediating Membrane Mental Depression Methodology Methods Modality Movement Disorders Mus Muscle Muscle Contraction Muscle Weakness Neurodegenerative Disorders Neurologic Neurons Noise Paralysed Parkinson Disease Patient Care Patients Peptides Permeability Pertussis Phase Pore Proteins Presynaptic Terminals Price Process Production Proteins Proteolysis Reproducibility SNAP receptor Sampling Serotyping Signal Transduction Silicon Dioxide Spasm Standardization Surface Sweating System Technology Testing Tetanus Therapeutic Therapeutic Uses Time Toxin Transmembrane Transport United States National Institutes of Health Validation Variant Vertebrates Work antitoxin aqueous base botulinum cell type cost improved in vivo ineffective therapies neurotransmission novel novel therapeutics polypeptide potency testing prevent programs prototype receptor research and development screening stability testing targeted cancer therapy uptake

项目摘要

Project Summary During this program, Electronic BioSciences, Inc. (EBS) will develop and validate its in-vitro, chip-based, picowell bilayer integrated assay (BP-IA) for characterizing the complete activity of botulinum toxin serotype A (BoNT/A) transmembrane toxin. A transmembrane toxin is a molecule that recognizes/targets a specific cell type via receptor-mediated targeting/endocytosis, forms a pore in the cell membrane, and transports itself or another molecule into the cell to disrupt cellular function, e.g., botulinum neurotoxin, tetanus, diphtheria, shiga, cholera, pertussis, etc. While these toxins are innately hazardous to human health, their inherent cell targeting and enzymatic capabilities can also be harnessed for therapeutic benefit. Today, the emerging therapeutic uses of toxins include but are not limited to the treatment of muscle spasms, wrinkles, excessive sweating, depression, anxiety, anorexia, neurodegenerative disorders (e.g., Parkinson’s disease), and targeted cancer therapy. However, the limitations of current toxin activity assessment methods have constrained the field. There is a need for a low cost, easy-to-use, rapid, highly sensitive, highly reproducible assay that is capable of individually quantifying the separate steps of the intoxication mechanism (i.e., the cell targeting/endocytosis and the intracellular enzymatic activity) to fully understand and utilize toxin functionality. The present standard for toxin activity assessments is the mouse intraperitoneal injection assay, which has numerous limitations, including price, variability, time, lack of sample quantification, and the utilization of live animals, in addition relying on a single endpoint determination that precludes assessment of the toxin’s mechanism. Unknown or poorly understood differences in the potency (or mode of action) of toxin-containing therapeutics can confound clinical dose findings, result in over or under dosing patients, and delay (or prohibit) the development and/or availability of new/novel therapeutics. EBS’ BP-IA technology will be capable of unprecedented toxin characterization in a low cost, easy-to-use, rapid, highly sensitive, highly reproducible, in vitro, chip-based platform. Furthermore, the methodology of the BP-IA is customizable such that the complete activity of any transmembrane toxin could be quantified. The development of the BP-IA under this Phase I program will be accomplished by developing and building an alpha prototype BP-IA device, and demonstrating the capability of the BP-IA device to quantitatively assess the potency of commercial BoNT/A therapeutic toxin formulations. Development of the BP-IA, a technology for which there is no equivalent commercially available and the future gold standard in toxin, biotherapeutics, cell-targeting, uptake/internal activity, and causation mechanism quantification, will directly enable the research and development of BoNT/A-based therapeutics, novel toxin agents/samples, the development of antitoxin agents, the detailed study of toxin and antitoxin mechanisms, the evaluation of the causative effects of experimental variables on each specific intoxication modality, and the assessment of toxin potency in general.

项目总结