First-in-Human Clinical Translation of a Near-Infrared, Nerve-Specific Fluorophore to Facilitate Tissue-Specific Fluorescence-Guided Surgery

项目摘要 安全有效的手术完成了所需的干预，使患者的 必要的病态。为了实现这一目标，外科医生必须区分不同的组织类型， 价值很高周围神经对于维持生命的功能至关重要。当被切断时， 神经愈合不良且很少恢复全部功能。医源性神经损伤可能会造成长期的、灾难性的 对病人的后果。标准白光可视化通常足以在正常情况下指导手术。 然而，解剖学在创伤、肿瘤、先前手术、先天性异常和放射治疗的情况下， 关键神经可能难以识别。此外，在最小程度上， 侵入性手术可能是具有挑战性的， 患者手术引导手术（FGS）是一种新生形式的手术导航，旨在增加患者的 通过使用组织增强对重要解剖结构的识别， 疾病特异性荧光团。迄今为止，FGS的研究主要集中在癌症的识别上; 相对较少的努力已被应用于正常结构的识别。因为他们的批评 重要性的功能和有限的愈合能力，成功翻译的神经特异性荧光团， 提供神经的视觉识别将导致手术方法的快速，全球性的转变， 医源性神经损伤的发病率。我们的研究小组合作开发了一种新的近红外 (NIR)在啮齿动物和猪中以高度特异性结合神经组织的荧光造影剂（IT 01 -08） 它与现有的临床FGS系统兼容。在拟议的研究中，我们将推进IT 01 -08 通过使用符合良好生产规范（GMP）的合成和配方， 方法和完成符合良好实验室规范（GLP）的临床前试验，使我们能够 成功申请IND批准，启动IT 01 -08的I期首次人体研究。我们集团有一个强大的 早期人类试验新型荧光团用于FGS的历史。我们将进一步提高分析 通过在接受下肢截肢的患者中进行本研究来执行IT 01 -08， 将能够切除病人的神经组织并从组织学上评估其毒性。我们的主要研究终点 将是手术信号检测和神经信号与背景组织比（SBR）>2。这项研究将提供： 合成GMP级配制、冻干、无菌IT 01 -08，用于全身给药，符合GLP 配制的IT 01 -08的临床前毒理学试验，以及I期数据，这些数据将使我们的团队能够进入I期 IT 01 -08的II试验。这项工作将导致一个有利的途径，临床翻译的荧光报告 在减少医源性神经损伤方面将是革命性的。

PROJECT SUMMARY Safe and effective surgery accomplishes the required intervention, leaving the patient with the minimum necessary morbidity. To accomplish this goal, surgeons must distinguish between tissue types, preserving those of high value. Peripheral nerves are critically important for life-sustaining functions. When severed, peripheral nerves heal poorly and rarely recover full function. Iatrogenic nerve injury can have long-term, catastrophic consequences for the patient. Standard white-light visualization is often adequate to guide surgery in normal anatomy, however, in the setting of trauma, tumors, prior surgery, congenital anomalies, and radiation therapy, critical nerves may be difficult to recognize. Additionally, positive identification of nerve tissue during minimally invasive surgery can be challenging due to the reliance on anatomical landmarks that are inconsistent across patients. Fluorescence-guided surgery (FGS) is a nascent form of surgical navigation that seeks to increase the safety and efficacy of surgery through enhanced recognition of important anatomical structures using tissue- and disease-specific fluorophores. To date, research in FGS has focused primarily on the identification of cancers; comparatively little effort has been applied to the identification of normal structures. Because of their critical importance to function and limited healing capacity, successful translation of a nerve-specific fluorophore to provide visual identification of nerves would lead to a rapid, global shift in surgical methods and a reduction in morbidity from iatrogenic nerve injuries. Our research group has cooperatively developed a new, near-infrared (NIR) fluorescent contrast agent (IT01-08) that binds to nerve tissue with high specificity in rodent and swine models and is compatible with existing clinical FGS systems. In the proposed studies, we will advance IT01-08 toward human use by scaling its synthesis and formulation using good manufacturing practice (GMP) compliant methods and completing good laboratory practice (GLP) compliant pre-clinical testing that will enable us to successfully apply for IND approval to initiate a Phase I, first-in-human study of IT01-08. Our group has a strong history of early human trialing of novel fluorophores for FGS. We will further enhance our ability to analyze the performance of IT01-08 by performing this study in patients undergoing lower extremity amputation, whereby we will be able to excise patient nerve tissue and evaluate it histologically for toxicity. Our primary study endpoints will be surgical signal detection and nerve signal-to-background tissue ratio (SBR) >2. This study will deliver: synthesis of GMP-grade formulated, lyophilized, sterile IT01-08 for systemic administration, GLP-compliant preclinical toxicology testing of formulated IT01-08, and Phase I data that will position our team to move to Phase II trialing of IT01-08. This work will result in an expedient pathway to clinical translation of a fluorescent reporter that will be revolutionary in its ability to reduce iatrogenic nerve injury.