Development and validation of an intraoperative imaging agent for the peripheral nervous system
周围神经系统术中显像剂的开发和验证
基本信息
- 批准号:10063737
- 负责人:
- 金额:$ 54.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-15 至 2024-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAmericanAnalgesicsAnimalsApplications GrantsAttentionBODIPYBindingBinding ProteinsBiologicalBloodBlood PressureCanis familiarisCardiacCardiovascular PhysiologyChronicClinicClinicalClinical TrialsContrast MediaDataDevelopmentDiseaseDisulfidesDoseDrug KineticsElectrocardiogramElectrophysiology (science)ExcisionFamily suidaeFluorescent DyesFoundationsFutureGoalsGrantHeartHepatocyteHumanIatrogenesisImageImage-Guided SurgeryIndividualInjectableInjectionsInjuryInterventionIntravenousIntuitionKnockout MiceLabelLeadLengthLesionLibrariesLocationMalignant - descriptorMaximum Tolerated DoseMedicalMindModelingModificationMonitorMorbidity - disease rateMusMuscleMuscle fasciculationMuscular AtrophyNerveNerve FibersNerve TissueNervous System TraumaNeuronsNeuropathyNoiseNude MiceOperative Surgical ProceduresOxygenPalpationParalysedPatientsPeptidesPerformancePeripheralPeripheral NervesPeripheral Nervous SystemPeripheral nerve injuryPeruPeruvianPharmacodynamicsPhase I Clinical TrialsPhysiologicalPhysiologyPlant RootsPlasma ProteinsPreparationPropertyReactionRecurrent Laryngeal NerveResearch ProposalsRespiratory physiologyRiskRodentSCN1A proteinSerumSignal TransductionSodium ChannelSpecificityStructureSurgeonSurgical OncologyTestingTimeTissuesToxic effectToxicologyTracerTransgenic OrganismsTranslatingTraumaTraumatic injuryUpper ExtremityValidationVenomsVisualWhole Bloodallodyniabaseclinical practicecohortdesignexperimental studyfluorescence imagingfluorophoreiatrogenic injuryimaging agentimaging systemimprovedin vivoin vivo imaging systeminhibitor/antagonistintravenous administrationlead candidatelipid solubilityloss of functionmalignant mouth neoplasmmembernear infrared dyenerve injurynovelpainful neuropathypatch clamppreservationresidencerespiratoryscaffoldsciatic nerveside effectstandard of caresurgery outcometumorvectorvirtual
项目摘要
Project Summary/Abstract
Twenty million Americans suffer from peripheral nerve injury caused by trauma and medical disorders, resulting
in a broad spectrum of potentially debilitating side effects. In one out of four cases, patients identify surgery as
the root cause of their nerve injury. Particularly during tumor resections or after traumatic injuries, tissue distortion
and poor visibility can challenge a surgeon's ability to precisely locate and preserve peripheral nerves. Intuitively,
surgical outcomes would improve tremendously if nerves could be highlighted using an exogeneous contrast
agent. In clinical practice, however, the current standard of care – visual examination and palpation – remains
unchanged.
The inability of surgeons to identify nerves during surgery represents an immense unmet clinical need, which we
propose to address within this application. We will develop and validate a translational fluorescent imaging agent
for the peripheral nervous system. In preparation for a clinical trial, we will show in mice and large animals that
the agent is safe for use in humans. Specifically, this proposal centers on Hsp1a, a peptide which we isolated
from the venom of a Peruvian tarantula, Homoeomma Spec. Peru, and which we found to be highly specific for
human Nav1.7. It has been shown that Nav1.7 is highly expressed in human peripheral nerve tissue. We believe
that a fluorescent Hsp1a will have tremendous value as an injectable, intraoperative guide during surgery, and
that the agent will provide surgeons with additional contrast, reducing iatrogenic injury and therefore surgical
morbidity.
To achieve this goal, we have assembled three specific aims (SAs), each of which will explore a distinct goal
toward showing that fluorescent Nav1.7 tracers can be translated to the clinic. In SA1, and supported by our
proof-of-principle data, we will synthesize a library of fluorescently labeled Hsp1a derivatives (n = 20), featuring
different fluorophores, attachment points and linker lengths. For all derivatives, we will determine the IC50 values
against Nav1.7 using patch-clamp electrophysiology; in SA2, pharmacokinetics and in vivo performance will be
determined using Nav1.7 expressing, tumor-bearing athymic nude mice and Nav1.7 deficient Scn9atm1Dgen/J mice.
For the most promising tracers (n = 3, based on IC50 and signal/noise ratios), we will test the minimum detectable
dose in cohorts of pigs. In SA3, we will interrogate the pharmacodynamic properties of the most promising Hsp1a
peptides. We will determine the maximum tolerated doses in mice while monitoring cardiovascular and
respiratory function. For the lead candidate, we will perform a 2-species GLP toxicity study (mice and dogs). If
successful, the current research proposal and generated data will form the foundation of a clinical phase I trial
with Hsp1a in oral cancer.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Thomas Reiner其他文献
Thomas Reiner的其他文献
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{{ truncateString('Thomas Reiner', 18)}}的其他基金
Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy
用于诊断和治疗的放射性碘标记多功能 PARP1 成像探针
- 批准号:
9177196 - 财政年份:2016
- 资助金额:
$ 54.22万 - 项目类别:
Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy
用于诊断和治疗的放射性碘标记多功能 PARP1 成像探针
- 批准号:
9306072 - 财政年份:2016
- 资助金额:
$ 54.22万 - 项目类别:
Bioorthogonal Strategies for Targeted PET Imaging Probe Development
靶向 PET 成像探针开发的生物正交策略
- 批准号:
8487906 - 财政年份:2013
- 资助金额:
$ 54.22万 - 项目类别:
Bioorthogonal Strategies for Targeted PET Imaging Probe Development
靶向 PET 成像探针开发的生物正交策略
- 批准号:
8829003 - 财政年份:2013
- 资助金额:
$ 54.22万 - 项目类别:
Bioorthogonal Strategies for Targeted PET Imaging Probe Development
靶向 PET 成像探针开发的生物正交策略
- 批准号:
8643230 - 财政年份:2013
- 资助金额:
$ 54.22万 - 项目类别:
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