Comprehensive Botulinum Characterization via the Bilayer Nanowell Integrated Assay
Comprehensive Botulinum Characterization via the Bilayer Nanowell Integrated Assay
批准号:
10480376
负责人:
Eric Ervin
金额:
$40.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-03-01 至 2024-02-29
关键词:
AcetylcholineAnimalsAnorexiaAnxietyAreaBindingBiological AssayBiological Response Modifier TherapyBiological SciencesBontoxilysinBotoxBotulinum ToxinsBreathingCell WallCell membraneCell physiologyCellsCessation of lifeCholeraClinicalComplexCosmeticsCytosolDevelopmentDevicesDiphtheriaDiseaseDoseElectrodesEndocytosisEndpoint DeterminationEnsureEnzymesEtiologyEvaluationFaceFatigueFluorescenceFocal DystoniasFormulationFutureGoldGrowthGuidelinesHealthHealthcareHourHumanIn VitroIndividualIntegral Membrane ProteinIntoxicationIntraperitoneal InjectionsIonsLeadLethal Dose 50LightLipid BilayersManufacturer NameMeasurementMeasuresMediatingMembraneMental DepressionMethodologyMethodsModalityMovement DisordersMusMuscleMuscle ContractionMuscle WeaknessNeurodegenerative DisordersNeurologicNeuronsNoiseParalysedParkinson DiseasePatient CarePatientsPeptidesPermeabilityPertussisPhasePore ProteinsPresynaptic TerminalsPriceProcessProductionProteinsProteolysisReproducibilitySNAP receptorSamplingSerotypingSignal TransductionSilicon DioxideSpasmStandardizationSurfaceSweatingSystemTechnologyTestingTetanusTherapeuticTherapeutic UsesTimeToxinTransmembrane TransportUnited States National Institutes of HealthValidationVariantVertebratesWorkantitoxinaqueousbasebotulinumcell typecostimprovedin vivoineffective therapiesneurotransmissionnovelnovel therapeuticspolypeptidepotency testingpreventprogramsprototypereceptorresearch and developmentscreeningstability testingtargeted cancer therapyuptake
中文摘要
项目摘要
在这个项目中,Electronic BioSciences,Inc. (EBS)将开发和验证其体外,基于芯片,
用于表征肉毒杆菌毒素血清型A(BoNT/A)的完全活性的双层整合测定(BP-IA)
跨膜毒素跨膜毒素是一种分子,其通过介导的免疫反应识别/靶向特定的细胞类型。
受体介导的靶向/内吞作用,在细胞膜上形成孔,并将其自身或另一个
分子进入细胞以破坏细胞功能,例如,肉毒杆菌神经毒素,破伤风,白喉,滋贺,霍乱,
虽然这些毒素天生对人类健康有害,但它们固有的细胞靶向和
酶的能力也可以用于治疗益处。今天,新兴的治疗用途,
毒素包括但不限于治疗肌肉痉挛,皱纹,过度出汗,抑郁,
焦虑、厌食、神经变性疾病(例如,帕金森氏病)和靶向癌症治疗。
然而,目前的毒素活性评估方法的局限性限制了该领域。有必要
对于低成本、易于使用、快速、高灵敏度、高重现性的测定,
量化中毒机制的各个步骤(即,细胞靶向/内吞作用和
细胞内酶活性)以充分理解和利用毒素功能。毒素的现行标准
活性评估是小鼠腹膜内注射测定,其具有许多局限性,包括
价格、可变性、时间、缺乏样本量化以及活动物的利用,此外,
单终点测定排除了毒素机制的评估。未知或较差
已知的含毒素治疗剂的效力(或作用模式)的差异可能混淆临床
剂量发现,导致患者给药过量或剂量不足,并延迟(或禁止)开发和/或可用性
新的/新颖的疗法。EBS的BP-IA技术将能够以前所未有的方式对毒素进行表征,
低成本、易于使用、快速、高灵敏度、高重现性、体外、基于芯片的平台。而且
BP-IA的方法学是可定制的,使得任何跨膜毒素的完整活性都可以被
量化。根据第一阶段计划,BP-IA的开发将通过开发和
构建alpha原型BP-IA设备,并证明BP-IA设备定量
评估商用BoNT/A治疗毒素制剂的效力。BP-IA的开发,a
这项技术目前还没有商业上可获得的同类产品,也是未来毒素的黄金标准,
生物治疗、细胞靶向、摄取/内部活性和因果机制定量,将直接
能够研究和开发基于BoNT/A的治疗剂、新型毒素剂/样品、
抗毒素药物的开发,毒素和抗毒素机制的详细研究,
实验变量对每种特定中毒方式的因果影响,以及毒素的评估
一般的力量。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Sequencing the Mono-Methylated Derivatives of Cytidine
-
批准号:10581093
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2023
-
负责人:Eric Ervin
-
依托单位:
Nanopores for Processing Proteins
-
批准号:10645984
-
项目类别:
-
资助金额:$40.73万
-
财政年份:2023
-
负责人:Eric Ervin
-
依托单位:
Point-of-Care Assay for Type 1 Diabetes Diagnosis and Prognostication
-
批准号:10721535
-
项目类别:
-
资助金额:$28.45万
-
财政年份:2023
-
负责人:Eric Ervin
-
依托单位:
Nanoscale Tools for Inosine Sequencing
-
批准号:10437956
-
项目类别:
-
资助金额:$100.0万
-
财政年份:2022
-
负责人:Eric Ervin
-
依托单位:
Nanoscale Tools for Inosine Sequencing
-
批准号:10651806
-
项目类别:
-
资助金额:$100.0万
-
财政年份:2022
-
负责人:Eric Ervin
-
依托单位:
Exonuclease Based Microsatellite Sequencing
-
批准号:10481241
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2022
-
负责人:Eric Ervin
-
依托单位:
Long-lived Platform Development for Exonuclease-Based Sequencing
-
批准号:10322603
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2021
-
负责人:Eric Ervin
-
依托单位:
Exonuclease Epigenetic Sequencing
-
批准号:10009454
-
项目类别:
-
资助金额:$89.7万
-
财政年份:2018
-
负责人:Eric Ervin
-
依托单位:
Nanopore Enabled Exonuclease Sequencing
-
批准号:9171771
-
项目类别:
-
资助金额:$22.5万
-
财政年份:2016
-
负责人:Eric Ervin
-
依托单位:
Bilayer Nanopore Integrated Assay
-
批准号:8831199
-
项目类别:
-
资助金额:$17.97万
-
财政年份:2015
-
负责人:Eric Ervin
-
依托单位:
Optimizing Nanopore Protein Interactions
-
批准号:8892399
-
项目类别:
-
资助金额:$23.5万
-
财政年份:2015
-
负责人:Eric Ervin
-
依托单位:
Identification and Quantification of Sequence Specific RNA Modifications via the Alpha-Hemolysin Latch Zone
-
批准号:8841921
-
项目类别:
-
资助金额:$21.57万
-
财政年份:2014
-
负责人:Eric Ervin
-
依托单位:
Encapsulated Lipid Bilayer Based Assay for Assessing Botulinum Neurotoxin Potency
-
批准号:8251686
-
项目类别:
-
资助金额:$18.49万
-
财政年份:2012
-
负责人:Eric Ervin
-
依托单位:
Nanopore Based Methods for Enantiomer Differentiation
-
批准号:8001793
-
项目类别:
-
资助金额:$16.68万
-
财政年份:2010
-
负责人:Eric Ervin
-
依托单位:
海外基金