Solid-state patch clamp platform to diagnose autism and screen for effective drug

描述(由申请人提供)：在过去的几年里，美国的自闭症谱系障碍(ASD)已经上升到大约每88人中就有1人患有自闭症，影响了整整一代儿童、家庭和社区。目前，大多数形式的自闭症的诊断都是基于三种行为症状，包括社交障碍、沟通困难和重复或刻板印象的行为，没有筛选或评估潜在药物治疗的量化指标。对这些患者的突触和神经元网络的电生理测量可能具有诊断、表征和分析潜在治疗策略的有效性的潜力。在这里，我们建议将一种变革性的技术应用于从患者来源的IPSC分化出的神经元的长期细胞内记录网络。为了实现这一目标，我们创造了一种由2D隐形电极阵列组成的固态设备，这些电极被动地位于神经元细胞膜内，能够在几天到几周的时间里同时记录多个相互连接的神经元的突触、神经元和网络属性。通过优化这些隐身探头的制造并将其转化为交钥匙装置，我们将评估该平台作为ASD诊断和研究工具的可行性。然后，我们建议使用这个创新的可扩展分析平台来表征从费兰-麦克德米德综合征患者的iPS细胞分化出的神经元、突触和网络签名，然后评估新兴药物疗法对异常签名正常化的有效性。如果成功，我们的固态平台可以转变为高通量筛查设备，使研究人员能够总结ASD的早期发展阶段，评估ASD突变和环境侮辱对神经元网络和突触功能的影响，并将其用作药物筛选、诊断和个性化治疗的工具。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) have risen to approximately 1 in 88 in the Unites States over the past years, affecting an entire generation of children, families and communities. Currently, the diagnosis for most forms of ASD is based on a triad of behavioral symptoms, including social impairments, communication difficulties, and repetitive or stereotyped behaviors, with no quantitative measures for screening or assessment of potential drug therapies. Electrophysiological measurements of synapses and neuronal networks from these patients may hold the potential for diagnosing, characterizing and analyzing the effectiveness of potential treatment strategies. Here, we propose to apply a transformative technology for the long-term intracellular recording networks of neurons differentiated from patient-derived iPSC. To accomplish this goal, we have created a solid-state device comprised of 2D arrays of Stealth electrodes that sit passively within the membrane of neuronal cells and have the capacity to record synaptic, neuronal and network properties of multiple interconnected neurons simultaneously for days to weeks. Through the optimization of the fabrication of these Stealth probes and the transformation into a turn-key device, we will evaluate the feasibility of this platform as a diagnostic and research tool for ASD. We then propose to use this innovative scalable analytical platform to characterize the neuronal, synaptic and network signatures of neurons differentiated from iPS cells derived from patients with Phelan-McDermid Syndrome and then assess the effectiveness of emerging drug therapies to normalize aberrant signatures. If successful, our solid-state platform can be transformed into a high-throughput screening device that will allow investigators to recapitulate early developmental stages of ASD and evaluate the effects of ASD mutations and environmental insults on neuronal network and synaptic function and utilize this as a tool for drug screening, diagnosis and personalized treatment.