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

项目总结 安全有效的手术完成了所需的干预，给患者留下了最少的干预。 必要的发病率。为了实现这一目标，外科医生必须区分组织类型，保留那些 有很高的价值。周围神经对于维持生命的功能至关重要。被切断时，外围设备 神经愈合不良，很少能完全恢复功能。医源性神经损伤可以有长期的、灾难性的 给病人带来的后果。标准白光可视化通常足以指导正常情况下的手术 然而，在创伤、肿瘤、先前的手术、先天性畸形和放射治疗的背景下，解剖学， 关键神经可能很难辨认。此外，神经组织的阳性识别在最低限度 侵入性手术可能是具有挑战性的，因为依赖于 病人。荧光引导手术(FGS)是一种新兴的手术导航形式，旨在增加 通过使用组织和组织增强对重要解剖结构的识别来实现手术的安全性和有效性 特定于疾病的荧光团。迄今为止，FGS的研究主要集中在癌症的识别上； 相对较少的努力被应用于正常结构的鉴定。因为他们的批评 功能的重要性和有限的愈合能力，成功地将神经特异性荧光团翻译成 提供神经的视觉识别将导致手术方法的快速、全球转变，并减少 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)荧光造影剂(IT01-08)，可与啮齿动物和猪的神经组织高度特异地结合 该系统适用于多种型号，并与现有的临床FGS系统兼容。在建议的研究中，我们会把IT01-08 通过使用符合GMP的良好制造规范(GMP)来缩放其合成和配方，从而达到人类使用的目的 方法和完成符合良好实验室规范(GLP)的临床前测试，使我们能够 成功申请IND批准，启动IT01-08的第一阶段人体研究。我们集团有一个强大的 早期人类试验用于FGS的新型荧光团的历史。我们将进一步提高分析 IT01-08通过在接受下肢截肢的患者中进行这项研究来执行，因此我们 将能够切除患者的神经组织，并对其进行组织学毒性评估。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率(SBR；2)。这项研究将提供： 符合GLP要求的GMP级配方、冻干、无菌全身给药IT01-08的合成 配方IT01-08的临床前毒理学测试，以及将使我们的团队进入阶段的第一阶段数据 II试行IT01-08。这项工作将为荧光报告的临床翻译提供一条便捷的途径 这将是其减少医源性神经损伤能力的革命性进展。

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.