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.

项目摘要 安全有效的手术可以完成所需的干预措施，使患者的最低限度 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，并保留这些类型 高价值。周围神经对于维持生命的功能至关重要。切断时，外围 神经愈合不佳，很少恢复全功能。医源性神经损伤可能会有长期的灾难性 对患者的后果。标准的白光可视化通常足以指导正常手术 然而，在创伤，肿瘤，先天手术，先天异常和放射治疗的情况下，解剖学 临界神经可能难以识别。另外，在最小化过程中对神经组织的阳性鉴定 由于依赖于整个跨度的解剖标志，侵入性手术可能具有挑战性 患者。荧光引导手术（FGS）是一种新生的外科导航形式，试图增加 通过使用组织和 疾病特异性荧光团。迄今为止，FGS的研究主要集中在癌症的鉴定上。 相对较少的努力已应用于正常结构的识别。因为他们的批判 对于功能和有限的愈合能力的重要性，神经特异性荧光团的成功翻译成 提供神经的视觉识别将导致手术方法的快速，全球变化，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个新的荧光团 （LGW16-03）在啮齿动物，猪和离体人体模型中与神经组织结合具有很高的特异性。在 拟议的补充研究，我们将通过完成临床前的lgw16-03进一步将LGW16-03推向人类使用 测试将使我们能够申请IND批准，以启动LGW16-03的第一阶段人类研究。我们的 小组对新型荧光团的早期人类试验有很强的历史。我们将进一步增强我们的能力 通过在接受下肢的患者中进行这项研究来分析LGW16-03的性能 截肢，我们将能够对患者神经组织进行切除并进行组织学评估毒性。我们的 主要研究终点将是手术信号检测和神经信号背景组织比率（SBR）> 2。 这项补充研究将提供：符合FDA的临床前毒理学测试我们优化的全身性 LGW16-03公式和第1阶段数据将使我们的团队转移到LGW16-03的2阶段试验。 这项工作将为荧光记者的临床翻译带来方便的途径 革命性的能力减少医源性神经损伤。

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。

• DOI: 10.1117/12.2650756
• 发表时间: 2023
• 期刊: Proceedings of SPIE--the International Society for Optical Engineering
• 作者: Henderson,EricR;Elliott,Jonathan;Jiang,Shudong;Gitajn,ILeah;Lee,John;Gibbs,Summer;Bouvet,Michael;Mahadevan-Jansen,Anita;Daly,Michael;Streeter,SamuelS;Paulsen,KeithD;Pogue,BrianW;Samkoe,KimberleyS;Singhal,Sunil
• 通讯作者: Singhal,Sunil

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。

• DOI: 10.1117/12.2650356
• 发表时间: 2023
• 期刊: Proceedings of SPIE--the International Society for Optical Engineering
• 作者: Bateman,LoganM;Hebert,KendraA;Streeter,SamuelS;Nunziata,JennaA;Barth,ConnorW;Wang,LeiG;Gibbs,SummerL;Henderson,EricR
• 通讯作者: Henderson,EricR

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。

• DOI: 10.1117/12.2650748
• 发表时间: 2023
• 期刊: Proceedings of SPIE--the International Society for Optical Engineering
• 作者: Hebert,KendraA;Bateman,Logan;Parker,Dylan;Nunziata,Jenna;Paydarfar,JosephA;Hong,Jennifer;Kerr,DarcyA;Zanazzi,GeorgeJ;Barth,ConnorW;Wang,Lei;Gibbs,SummerL;Henderson,EricR
• 通讯作者: Henderson,EricR