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: 10633513
• 负责人: Connor William Barth
• 金额: $ 21.9万
• 依托单位: INHERENT TARGETING, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633513
• 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.

项目摘要 医源性神经损伤是最令人恐惧的手术并发症之一。神经至关重要 对于大多数组织和神经损伤的功能，可能导致永久性残疾。通常进行手术 在美国，每年大约有4000万次手术，最多造成60万个医源性神经损伤。 神经损伤特别困扰的一种过程是从根治性的前列腺切除术（RP），在其中发生神经损伤 在多达60％的患者中，进行超过30年的神经保障手术方法的实践。目前在那里 没有临床认可的技术来改善手术期间神经组织的视觉识别，离开 外科医生在很大程度上依靠解剖学知识来定位肉眼无形的小或埋葬的神经。 荧光引导手术（FGS）是一个新生的领域，在改善手术结局方面表现出效率 用于癌症切除和正常的解剖结构，使用分子靶向荧光团和商业 FGS成像系统。我们已经开发了几种针对的，有针对性的，近红外（NIR）的荧光团 具有高亲和力的神经组织 - 迄今为止最有前途的是IT01-08。 IT01-08专门标记啮齿动物， 全身给药后的猪和犬神经，并证明了体内人体的交叉反应性 标本染色。值得注意的是，我们已经开发了一个IT01-08衍生物的库，其中一些显示了 初步测试中的水溶解度和毒性概况极大地提高了，增加了观察到的逆境 效应水平（NOAEL）剂量2-10x。需要最终溶解度，毒理学和药理学测试才能选择 IT1-08及其衍生物的铅化合物。铅化合物选择后，临床翻译 最佳的NIR神经特异性荧光团将在神经治疗RP期间增强神经识别，从而导致 神经损伤减少并改善患者结局。这项研究的直接里程碑包括 - 第一阶段：（1） 选择用于翻译的临床可行的NIR神经特异性荧光团，（2）相关药代动力学，剂量 药物宏观动力学和生物分布定量和（3）初步毒理学分析以指导 研究新药（IND）增强研究。第二阶段：（4）合成的良好实验室实践（GLP） （5）GLP两种药理学和毒理学（Pharm/Tox）研究的荧光团和配方产品研究 促进（6）成功地向FDA应用。我们的长期战略计划是发展我们的NIR神经 - 特定的荧光团用于人类使用，以增强具有广泛临床的神经的识别和保存 对所有手术亚专科的影响。拟议的目标的完成将建立对这些目标的临床前测试 有希望的紧张突出媒介对人类的第一次试验，并为行业奠定了坚实的基础 临床翻译的伙伴关系和投资。