Administrative Supplement - First-in-human clinical translation of a near-infrared, nerve-specific fluorophore to facilitate tissue-specific fluorescence-guided surgery

行政补充-近红外神经特异性荧光团的首次人体临床转化，以促进组织特异性荧光引导手术

• 批准号: 10862946
• 负责人: Summer Lynne Gibbs
• 金额: $ 14.61万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10862946
• 关键词: Address; Administrative Supplement; Amputation; Anatomy; Binding; Clinical Research; Data; Detection; Disease; Family suidae; Formulation; Goals; Histologic; Human; Iatrogenesis; Injury; Intervention; Life; Light; Lower Extremity; Malignant Neoplasms; Medical; Methods; Morbidity - disease rate; Nerve; Nerve Tissue; Operative Surgical Procedures; Pathway interactions; Patient Care; Patients; Performance; Peripheral Nerves; Phase; Positioning Attribute; Preclinical Testing; Procedures; Radiation therapy; Recording of previous events; Refractory; Reporter; Research; Rodent; Safety; Signal Transduction; Specific qualifier value; Specificity; Structure; Surgeon; Testing; Tissues; Toxic effect; Toxicology; Translations; Trauma; Visual; Visualization; Work; clinical translation; comparative; congenital anomaly; cost; first-in-human; fluorescence-guided surgery; fluorophore; healing; human model; human study; minimally invasive; nerve injury; neurotransmission; novel; phase II trial; pre-clinical; preservation; pressure; tumor

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.

项目概要 安全有效的手术完成了所需的干预，为患者留下了最少的损失 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，保留这些组织 具有高价值。周围神经对于维持生命的功能至关重要。当切断时，外围 神经愈合不良，很少恢复全部功能。医源性神经损伤可能会造成长期的、灾难性的后果 对患者造成的后果。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、既往手术、先天性异常和放射治疗的情况下，解剖学 关键神经可能很难识别。此外，在最低限度期间对神经组织进行积极识别 由于依赖于不同部位不一致的解剖标志，侵入性手术可能具有挑战性 患者。荧光引导手术（FGS）是一种新兴的手术导航形式，旨在增加 通过使用组织和增强对重要解剖结构的识别来提高手术的安全性和有效性 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。 在识别正常结构方面所做的努力相对较少。因为他们的批评 对功能的重要性和有限的治愈能力，成功地将神经特异性荧光团转化为 提供神经的视觉识别将导致手术方法的快速、全球性转变并减少 医源性神经损伤的发病率。我们课题组合作开发了一种新型荧光团 (LGW16-03) 在啮齿动物、猪和离体人类模型中以高特异性与神经组织结合。在 拟议的补充研究，我们将通过完成临床前进一步推进 LGW16-03 走向人类使用 测试将使我们能够申请 IND 批准，以启动 LGW16-03 的第一阶段首次人体研究。我们的 该小组在新型荧光团的早期人体试验方面有着悠久的历史。我们将进一步增强我们的能力 通过在接受下肢手术的患者中进行这项研究来分析 LGW16-03 的性能 截肢，我们将能够切除患者的神经组织并对其进行组织学评估以评估其毒性。我们的 主要研究终点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： 对我们优化的系统进行符合 FDA 标准的临床前毒理学测试 LGW16-03 配方和第一阶段数据将使我们的团队进入 LGW16-03 的第二阶段试验。 这项工作将为荧光报告基因的临床转化提供一条便捷途径， 其减少医源性神经损伤的能力具有革命性。

项目成果

Proceduralist criteria for evaluating interface utility of novel imaging modalities in early phase clinical trials: evaluating the need for standardized criteria.

评估早期临床试验中新型成像方式的界面实用性的程序主义标准：评估标准化标准的必要性。

• 发表时间: 2023
• 作者: Henderson, Eric R;Elliott, Jonathan;Jiang, Shudong;Gitajn, I Leah;Lee, John;Gibbs, Summer;Bouvet, Michael;Mahadevan;Daly, Michael;Streeter, Samuel S;Paulsen, Keith D;Pogue, Brian W;Samkoe, Kimberley S;Singhal, Sunil
• 通讯作者: Singhal, Sunil

First demonstration of a novel nerve-targeting fluorophore in a cohort of ex vivo human tissues.

首次在一组离体人体组织中展示新型神经靶向荧光团。

• 发表时间: 2023
• 作者: Hebert, Kendra A;Bateman, Logan;Parker, Dylan;Nunziata, Jenna;Paydarfar, Joseph A;Hong, Jennifer;Kerr, Darcy A;Zanazzi, George J;Barth, Connor W;Wang, Lei;Gibbs, Summer L;Henderson, Eric R
• 通讯作者: Henderson, Eric R

Use of Freshly Amputated Human Limbs for Pre-Clinical Evaluation of Molecular-Targeted Fluorescent Probes.

使用刚截肢的人体肢体进行分子靶向荧光探针的临床前评估。

• 发表时间: 2023
• 作者: Bateman, Logan M;Hebert, Kendra A;Streeter, Samuel S;Nunziata, Jenna A;Barth, Connor W;Wang, Lei G;Gibbs, Summer L;Henderson, Eric R
• 通讯作者: Henderson, Eric R