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：
10375544
负责人：
Nagavarakishore Pillarsetty
金额：
$ 52.19万
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/10375544
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 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 intravenous administration lead candidate lipid solubility loss of function malignant mouth neoplasm member mouse model near infrared dye nerve injury novel painful neuropathy patch clamp peripheral nerve damage porcine model 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.

项目摘要/摘要两千万美国人因创伤和医疗疾病造成的周围神经伤害，导致在广泛的潜在使人衰弱的副作用中。在四分之一病例中，患者将手术视为其神经损伤的根本原因。特别是在肿瘤切除术或创伤后，组织失真不良的能见度可以挑战外科医生精确定位和保存周围神经的能力。直觉，如果可以使用外抗对比度突出神经，手术结果将大大改善代理人。然而，在临床实践中，当前的护理标准 - 视觉检查和触诊 - 仍然存在不变。外科医生无法在手术过程中识别神经代表了巨大的未满足的临床需求，我们在此应用程序中解决的建议。我们将开发并验证翻译的荧光成像剂对于周围神经系统。为了准备临床试验，我们将在小鼠和大型动物中展示代理可以安全地用于人类。具体而言，该建议集中于HSP1A，这是我们隔离的肽来自秘鲁狼蛛的毒液，同性恋Spec。秘鲁，我们发现它非常具体人类NAV1.7。已经表明，NAV1.7在人外周神经组织中高度表达。我们相信荧光Hsp1a将具有巨大的价值作为手术期间的可注射术中指南，并且代理人将为外科医生提供额外的对比度，减少医源性损伤，因此手术发病率。为了实现这一目标，我们组装了三个特定目标（SAS），每个目标都将探索一个独特的目标要显示荧光NAV1.7示踪剂可以转化为诊所。在SA1中，并得到我们的支持原理数据证明，我们将合成一个荧光标记的HSP1A衍生物（n = 20）的库不同的荧光团，附着点和接头长度。对于所有衍生物，我们将确定IC50值使用贴片钳电生理学对抗NAV1.7；在SA2中，药代动力学和体内性能将是使用NAV1.7表达，含有肿瘤的裸体裸鼠和NAV1.7缺陷SCN9ATM1DGEN/J小鼠确定。对于最有前途的示踪剂（基于IC50和信号/噪声比），我们将测试可检测到的最小值猪群中的剂量。在SA3中，我们将询问最有希望的HSP1A的药效学特性肽。我们将在监测心血管和呼吸功能。对于主要候选人，我们将进行两种种类的GLP毒性研究（小鼠和狗）。如果成功的，当前的研究建议和生成的数据将构成I阶段试验的基础与Hsp1a进行口腔癌。