Administrative Supplement - 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荧光团 （LGW 16 -03），其在啮齿动物、猪和离体人模型中以高特异性结合神经组织。在 建议的补充研究，我们将通过完成临床前研究，进一步推进LGW 16 -03的人类使用 这将使我们能够申请IND批准，以启动LGW 16 -03的1期首次人体研究。我们 该小组在早期人类试验新型荧光团方面有着悠久的历史。我们会进一步提升能力， 通过在接受下肢手术的患者中进行本研究，分析LGW 16 -03的性能 截肢，我们将能够切除患者的神经组织，并从组织学上评估其毒性。我们 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。 这项补充研究将提供：符合FDA要求的临床前毒理学试验， LGW 16 -03制剂和1期数据，这些数据将使我们的团队能够进入LGW 16 -03的2期试验。 这项工作将导致一个有利的途径，临床翻译的荧光报告，将是 革命性的减少医源性神经损伤的能力。

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 fluorophore (LGW16-03) that binds to nerve tissue with high specificity in rodent, swine, and ex vivo human models. In the proposed supplement studies, we will further advance LGW16-03 toward human use by completing pre-clinical testing that will enable us to apply for IND approval to initiate a phase 1, first-in-human study of LGW16-03. Our group has a strong history of early human trialing of novel fluorophores. We will further enhance our ability to analyze the performance of LGW16-03 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 supplemental study will deliver: an FDA-compliant preclinical toxicology testing of our optimized systemic LGW16-03 formulation, and phase 1 data that will position our team to move to phase 2 trialing of LGW16-03. 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.