Clinical Translation of Near Infrared Nerve-Specific Fluorophores for Nerve-sparing Prostatectomy

近红外神经特异性荧光团在保留神经的前列腺切除术中的临床转化

• 批准号: 10081607
• 负责人: Connor William Barth
• 金额: $ 22.47万
• 依托单位: INHERENT TARGETING, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081607
• 关键词: Acute; Affect; Affinity; Anatomy; Biodistribution; Blood; Body Weight; Canis familiaris; Chemicals; Clinical; Clinical Research; Clinical Trials; Contracts; Contrast Media; Dose; Drug Kinetics; Excision; Eye; Family suidae; Formulation; Foundations; Freeze Drying; Fright; Human; Iatrogenesis; Image; Image-Guided Surgery; Intravenous; Investigational Drugs; Investigational New Drug Application; Investments; Knowledge; Label; Laboratories; Lead; Libraries; Malignant Neoplasms; Methods; Molecular Target; Mus; Nerve; Nerve Tissue; Nerve-Sparing Prostatectomy; No-Observed-Adverse-Effect Level; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Phase; Preclinical Testing; Procedures; Radical Prostatectomy; Rattus; Rivers; Rodent; Services; Solubility; Specificity; Specimen; Stains; Sterility; Strategic Planning; Structure; Surgeon; Surgical complication; Technology; Testing; Time; Toxic effect; Toxicology; Translations; United States; Visual; Visualization; clinical translation; cross reactivity; design; disability; first-in-human; fluorescence-guided surgery; fluorophore; good laboratory practice; imaging system; improved; industry partner; lead candidate; nerve damage; nerve injury; neurotransmission; operation; pre-clinical; preservation; surgery outcome; tissue injury; water solubility

PROJECT SUMMARY Iatrogenic nerve injury is one of the most feared complications of surgery. Nerves are critically important to the function of most tissues and nerve injury can lead to permanent disability. Surgery is performed commonly in the U.S. with approximately 40 million operations annually, incurring up to 600,000 iatrogenic nerve injuries. One procedure particularly plagued by nerve damage is radical prostatectomy (RP), where nerve damage occurs in up to 60% of patients, despite the practice of nerve sparing surgical methods for >30 years. At present there is no clinically approved technology to improve visual recognition of nerve tissue during surgery, leaving surgeons to rely largely on anatomical knowledge to locate small or buried nerves invisible to the naked eye. Fluorescence-guided surgery (FGS) is a nascent field with demonstrated efficacy in improving surgical outcomes for cancer resection and normal anatomy preservation using molecularly-targeted fluorophores and commercial FGS imaging systems. We have developed several first-in-kind, targeted, near-infrared (NIR) fluorophores that label nerve tissue with high affinity—to date the most promising is IT01-08. IT01-08 specifically labels rodent, swine and canine nerves following systemic administration and demonstrates cross reactivity in ex vivo human specimen staining. Notably, we have developed a library of IT01-08 derivatives, several of which have displayed vastly improved water solubilities and toxicity profiles in preliminary testing, increasing the no observed adverse effect level (NOAEL) doses 2-10X. Final solubility, toxicology, and pharmacology testing is required to select a lead compound from IT01-08 and its derivatives. Following lead compound selection, clinical translation of the optimal NIR nerve-specific fluorophore will enhance nerve identification during nerve-sparing RP, resulting in reduced nerve injury and improved patient outcomes. This study’s immediate milestones include – Phase I: (1) selection of a clinically viable, NIR nerve-specific fluorophore for translation, (2) relevant pharmacokinetics, dose ranging pharmacodynamics, and biodistribution quantification, and (3) preliminary toxicology analysis to guide investigational new drug (IND)-enabling studies. Phase II: (4) good laboratory practice (GLP) synthesized fluorophore and formulation product for, (5) a GLP two-species pharmacology and toxicology (pharm/tox) study facilitating, (6) a successful IND application to the FDA. Our long-term strategic plan is to develop our NIR nerve- specific fluorophores for human use to enhance the identification and preservation of nerves with broad clinical impact for all surgical subspecialties. Completion of the proposed aims will establish pre-clinical testing of these promising nerve highlighting agents towards first-in-human trials and provide a strong foundation for industry partnerships and investment for clinical translation.

项目概要 医源性神经损伤是手术中最可怕的并发症之一。神经至关重要 大多数组织和神经损伤的功能可能导致永久性残疾。手术是常见的 在美国，每年约有 4000 万例手术，造成多达 60 万例医源性神经损伤。 一种特别受神经损伤困扰的手术是根治性前列腺切除术（RP），其中会发生神经损伤 尽管神经保留手术方法的实践已超过 30 年，但仍有高达 60% 的患者出现这种情况。目前有 目前还没有临床批准的技术可以提高手术期间神经组织的视觉识别能力，因此 外科医生主要依靠解剖学知识来定位肉眼看不见的小神经或埋藏神经。 荧光引导手术 (FGS) 是一个新兴领域，已证明可有效改善手术结果 使用分子靶向荧光团和商业荧光团进行癌症切除和正常解剖结构保存 FGS 成像系统。我们开发了几种同类首创的靶向近红外 (NIR) 荧光团， 以高亲和力标记神经组织——迄今为止最有前途的是IT01-08。 IT01-08专门标记啮齿动物， 全身给药后对猪和犬神经产生影响，并在离体人体中表现出交叉反应性 标本染色。值得注意的是，我们开发了一个 IT01-08 衍生品库，其中一些已经展示 在初步测试中大大改善了水溶性和毒性特征，增加了未观察到的不良反应 效应水平 (NOAEL) 剂量 2-10X。需要进行最终溶解度、毒理学和药理学测试来选择 IT01-08 的先导化合物及其衍生物。在选择先导化合物后，将其进行临床转化 最佳 NIR 神经特异性荧光团将增强神经保护 RP 期间的神经识别，从而导致 减少神经损伤并改善患者预后。这项研究的直接里程碑包括 – 第一阶段：(1) 选择临床上可行的近红外神经特异性荧光团进行翻译，(2) 相关药代动力学、剂量 范围药效学和生物分布定量，以及（3）初步毒理学分析以指导 研究性新药 (IND) 启用研究。第二阶段：（4）良好实验室规范（GLP）综合 用于 (5) GLP 两物种药理学和毒理学（药物/毒理学）研究的荧光团和制剂产品 促进，(6) 成功向 FDA 申请 IND 申请。我们的长期战略计划是发展我们的近红外神经- 人类使用的特定荧光团可增强神经的识别和保存，具有广泛的临床应用 对所有外科亚专业的影响。完成拟议的目标将对这些进行临床前测试 有望进行首次人体试验的神经突出剂，并为行业提供坚实的基础 临床转化的合作伙伴关系和投资。