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

项目总结 药物开发流水线受到不可接受的流失率的困扰，很大程度上是由于 在临床前发展阶段没有被识别出来。虽然周围神经病仍然是一种常见的毒物 新药的副作用，这种毒性通常只在晚期临床前开发或 甚至是早期的临床试验。药物引起的神经毒性是由药物的非靶点效应引起的 到感觉、运动和认知缺陷。虽然很少致命，但药物引起的周围神经毒性可导致 永久性神经损伤，在某些情况下可能是剂量限制的副作用，导致患者减少 剂量或完全停止治疗。“单芯片器官”技术正在稳步地被 制药行业，因为它们有能力在临床前开发期间帮助降低先导化合物的风险。 为此，我们论证了技术上的可行性和成功的商业部署 外周“芯片上的神经”，由一个3D神经元/神经胶质球体突起致密的轴突纤维束组成， 类似于周围神经解剖。前几个获奖阶段的进展有力地证明了 应用符合形态和生理条件的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了 药物引起的神经毒性，表现为与临床神经病理学相似的方式。有价值的反馈 来自行业早期采用者的数据使我们能够修正先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。这项提议的目的是 制造具有集成微电极的客户就绪的多孔器件，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。完成这些目标将 将这项技术定位为可扩展实施，使我们能够为制药行业提供广泛的平台 在临床前药物开发过程中更早寻求关于周围神经病的信息的公司 比目前可能的要多。

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.