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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：
Thomas Reiner
金额：
$ 54.22万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
https://reporter.nih.gov/project-details/10063737
关键词：
Address American Analgesics Animals Applications Grants Attention BODIPY Binding Binding Proteins Biological Blood Blood Pressure Canis familiaris Cardiac Cardiovascular Physiology Chronic Clinic Clinical Clinical Trials Contrast Media Data Development Disease Disulfides Dose Drug Kinetics Electrocardiogram Electrophysiology (science)Excision Family suidae Fluorescent Dyes Foundations Future Goals Grant Heart Hepatocyte Human Iatrogenesis Image Image-Guided Surgery Individual Injectable Injections Injury Intervention Intravenous Intuition Knockout Mice Label Lead Length Lesion Libraries Location Malignant - descriptor Maximum Tolerated Dose Medical Mind Modeling Modification Monitor Morbidity - disease rate Mus Muscle Muscle fasciculation Muscular Atrophy Nerve Nerve Fibers Nerve Tissue Nervous System Trauma Neurons Neuropathy Noise Nude Mice Operative Surgical Procedures Oxygen Palpation Paralysed Patients Peptides Performance Peripheral Peripheral Nerves Peripheral Nervous System Peripheral nerve injury Peru Peruvian Pharmacodynamics Phase I Clinical Trials Physiological Physiology Plant Roots Plasma Proteins Preparation Property Reaction Recurrent Laryngeal Nerve Research Proposals Respiratory physiology Risk Rodent SCN1A protein Serum Signal Transduction Sodium Channel Specificity Structure Surgeon Surgical Oncology Testing Time Tissues Toxic effect Toxicology Tracer Transgenic Organisms Translating Trauma Traumatic injury Upper Extremity Validation Venoms Visual Whole Blood allodynia base clinical practice cohort design experimental study fluorescence imaging fluorophore iatrogenic injury imaging agent imaging system improved in vivo in vivo imaging system inhibitor/antagonist intravenous administration lead candidate lipid solubility loss of function malignant mouth neoplasm member near infrared dye nerve injury novel painful neuropathy patch clamp preservation residence respiratory scaffold sciatic nerve side effect standard of care surgery outcome tumor vector virtual

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