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

项目摘要 医源性神经损伤是外科手术最令人担心的并发症之一。神经是至关重要的 对大部分组织和神经功能的损伤可导致永久性残疾。手术通常是 在美国，每年约有4000万例手术，导致多达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椎间盘切除术（RP）， 在高达60%的患者中，尽管神经保留手术方法的实践超过30年。现时 没有临床批准的技术来改善手术期间神经组织的视觉识别， 外科医生在很大程度上依靠解剖学知识来定位肉眼看不见的细小或埋藏的神经。 手术引导手术（FGS）是一个新兴领域，在改善手术结果方面具有显著疗效 用于癌症切除和正常解剖结构的保存，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第一种，有针对性的，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IT 01 -08。IT 01 -08专门标记啮齿动物， 猪和犬神经，并在离体人中显示交叉反应性 标本染色。值得注意的是，我们已经开发了一个IT 01 -08衍生物的文库，其中几个已经显示出 在初步测试中，大大改善了水溶性和毒性，增加了未观察到的不良反应。 作用水平（NOAEL）剂量2- 10倍。需要进行最终溶解度、毒理学和药理学试验，以选择 来自IT 01 -08的先导化合物及其衍生物。在先导化合物选择之后， 最佳的NIR神经特异性荧光团将在神经保留RP期间增强神经识别，导致 减少神经损伤并改善患者预后。本研究的近期里程碑包括-I期：（1） 选择临床上可行的NIR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，和（3）初步毒理学分析，以指导 研究性新药（IND）启动研究。第二阶段：（4）合成药物非临床研究质量管理规范（GLP） 荧光团和制剂产品，（5）GLP两种药理学和毒理学（pharm/tox）研究 （6）向FDA成功申请IND。我们的长期战略计划是发展我们的近红外神经- 用于人类的特异性荧光团，以增强具有广泛临床意义的神经的识别和保存 对所有外科专科的影响。完成拟议的目标将建立这些的临床前测试 有前途的神经突出剂进行首次人体试验，并为工业提供坚实的基础 临床翻译的合作伙伴关系和投资。

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.