Peripheral Nerve-on-a-chip for Predictive Preclinical Pharmaceutical Testing

项目摘要 药物开发管道受到不可接受的损耗率的困扰，这在很大程度上是由于毒性， 未在临床前开发阶段确定。虽然周围神经病变仍然是一种常见的毒性 新药的副作用，这种毒性通常仅在后期临床前开发期间首次发现， 甚至是早期的临床试验药物诱导的神经毒性是由药物的脱靶效应引起的， 感觉运动和认知缺陷虽然很少致命，但药物诱导的外周神经毒性可导致 永久性神经损伤，在某些情况下可能是剂量限制性副作用，导致患者减少 剂量或完全停止治疗。“芯片上器官”技术正逐渐被 由于其在临床前开发过程中帮助降低先导化合物风险的能力， 为此，我们展示了技术可行性和成功的商业部署， 外周“神经芯片”，由3D神经元/神经胶质球状体投射致密轴突纤维束组成， 类似于周围神经解剖学。前几个授标阶段的进展有力地证明了 使用微工程神经组织的可行性， 类似于临床试验的测量。体外结构和功能分析的使用导致 药物诱导的神经毒性，表现为类似于临床神经病理学的方式。有价值的反馈 来自行业早期采用者的经验使我们能够修改以前的假设，并解决许多技术问题。 挑战，我们现在寻求在商业规模上部署这项技术。这项建议的目的是 制造具有集成微电极的客户准备好的多孔装置，并提供更完整的 使用高通量转录组学对我们的模型进行生物学表征。实现这些目标将 将该技术定位为可扩展的实施，使我们能够为制药行业广泛提供平台。 在临床前药物开发过程早期寻求周围神经病变信息的公司 比目前可能的。

PROJECT SUMMARY The drug development pipeline is plagued by unacceptable rates of attrition due in large part to toxicities that are not identified in pre-clinical stages of development. While peripheral neuropathy remains a common toxic side-effect of new drugs, such toxicity is typically only first identified during late-stage preclinical development or even early clinical trials. Drug-induced neurotoxicity is caused by off-target effects of pharmaceuticals that lead to sensory, motor, and cognitive deficits. While rarely fatal, drug-induced peripheral neurotoxicity can lead to permanent nerve damage and in some cases can be a dose-limiting side effect, leading patients to reduce dosage or stop treatment altogether. “Organ-on-a-chip” technologies are steadily becoming adopted by the pharmaceutical industry because of their ability to help de-risk lead compounds during pre-clinical development. Towards that end, we demonstrated the technical feasibility and successful commercial deployment of a peripheral “nerve-on-a-chip,” consisting of a 3D neuronal/glial spheroid projecting dense axonal fiber tracts, resembling peripheral nerve anatomy. Progress during the prior award phases strongly demonstrated the feasibility of using microengineered neural tissues that are amenable to morphological and physiological measurements analogous to those of clinical tests. The use of structural and functional analyses in vitro led to drug-induced neural toxicity that manifested in ways analogous to clinical neuropathology. Valuable feedback from industry early adopters has enabled us to revise previous assumptions and resolve many technical challenges, and we now seek to deploy the technology at a commercial scale. The aims of this proposal are to manufacture customer-ready multiwell devices with integrated microelectrodes, and to provide a more complete biological characterization of our model using high-throughput transcriptomics. Completion of these aims will position this technology for scalable implementation, enabling us to offer the platform widely to pharmaceutical companies seeking information about peripheral neuropathy earlier in the preclinical drug development process than currently possible.