Remote Electromagnetic Control of Neural Activity for Treatment of Parkinson's Disease

神经活动的远程电磁控制治疗帕金森病

• 批准号: 9890014
• 负责人: Jonathan S. Dordick
• 金额: $ 66万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890014
• 关键词: Address; Albumins; Anterior; Apoptosis; Basic Science; Behavior; Binding; Biological Assay; Biomedical Engineering; Bradykinesia; Cell physiology; Cells; Chloride Channels; Chronic; Chronic Disease; Clinical Research; Cochlear Implants; Collaborations; Deep Brain Stimulation; Dependovirus; Development; Device or Instrument Development; Devices; Directed Molecular Evolution; Disease; Electrodes; Electromagnetic Energy; Electromagnetic Fields; Electromagnetics; Electrophysiology (science); Engineering; Enzymes; Ferritin; Frequencies; Future; Gait; Gene Activation; Gene Delivery; Gene Expression; Geometry; Hepatocyte; Human; Hydroxydopamines; Implant; Implanted Electrodes; In Vitro; Ion Channel; Iron; Knock-in; Knock-in Mouse; Laboratories; Lead; Legal patent; Light; Limb structure; Liver; Magnetism; Mechanics; Metabolism; Methodology; Methods; Molecular; Morphology; Motion; Motor Cortex; Mouse Strains; Mus; Mutation; Nervous system structure; Neural Inhibition; Neurons; Nucleosome Core Particle; Outcome; Pacemakers; Parkinson Disease; Partner in relationship; Patients; Population; Preclinical Testing; Predisposition; Process; Production; Property; Proteins; Publications; Radio Waves; Recombinant adeno-associated virus (rAAV); Recording of previous events; Regulation; Rotation; Safety; Site; Structure of subthalamic nucleus; System; TRPV1 gene; Technology; Temperature; Testing; Tremor; Variant; Work; base; cell type; design; dopaminergic neuron; efficacy study; gene therapy; improved; in vitro activity; in vivo; instrument; instrumentation; iron oxide nanoparticle; magnetic field; minimally invasive; motor symptom; mouse model; mutant; nanobiomaterial; nanoparticle; nervous system disorder; nestin protein; neural circuit; neuroregulation; neurotropic; new technology; novel; optogenetics; overexpression; personalized medicine; portability; pre-clinical; preclinical efficacy; preclinical evaluation; preclinical safety; preclinical study; prototype; radio frequency; reduce symptoms; relating to nervous system; response; safety study; side effect; symptom treatment; technology validation; tool; wearable device

Project Summary In this collaborative and interdisciplinary application, we propose to develop further a novel non-invasive method for cell regulation (NICR) that is suitable for preclinical proof of concept studies. This technology potentially could be used to treat neurologic diseases and provide a less invasive alternative to deep brain stimulation (DBS) or optogenetics. We thus propose to refine the technology and develop a prototype device to test the use of NICR for the treatment of symptoms of Parkinson's Disease (PD) in mice. Cell activity is controlled by two components; the iron binding ferritin protein that spontaneously forms 5 nm iron nanoparticles and TRPV1, a temperature and mechano-sensitive channel. By tethering ferritin to TRPV1, one can gate the channel with radiofrequency (RF) (which heat or induce mechanical motion of ferritin) or a magnet (which induces motion). The method has been shown to be capable of controlling neural activity in vitro and in vivo, the latter by increasing neural firing. In addition, we have introduced a mutation into TRPV1 that converts it into a chloride channel, and the use of the mutant channel makes it possible to inhibit neural activity using electromagnetic waves (e.g., RF). Because the system is genetically encoded, one can regulate the activity of cells into which the two protein components of the system have been delivered by recombinant Adeno- Associated Virus (AAV) strains. AAV has been used in numerous human studies including patients with PD. Thus NICR could provide a less invasive alternative to implanted electrodes (DBS) or implanted light devices (optogenetics) for the modulation of neural activity (deep brain stimulation) and also be used to simultaneously control several different nodes in a neural circuit. In this application, we propose a set of preclinical proof-of-concept studies for the treatment of PD including: 1) refinement of the technology to improve its efficiency and to create suitable AAV strains to ameliorate the symptoms of PD. We also propose to increase the sensitivity of the system by using channels that can be gated with lower field strength and by identifying variants of ferritin with enhanced sensitivity to an electromagnetic field; 2) development of a prototype device that would create local electromagnetic fields of suitable strength with the aim of enabling the use of the method in routine laboratory settings and ultimately as a portable/wearable device; 3) testing the ability of the improved method and suitable instrumentation to alleviate the symptoms of PD in mice; and 4) creating knockin mice with cre dependent expression of the constructs to assess the safety of long term TRPV1 and ferritin expression. The validation of this technology could also lead to its use for the treatment of other diseases at sites within and outside the nervous system to either increase or decrease cell activity or regulate protein production. Finally, the further development of NICR could impact basic research by allowing the non-invasive activation or inhibition of cells by simply mating genetically modified mice and exposing them to RF or magnetic fields.

项目概要 在这种协作和跨学科应用中，我们建议进一步开发一种新型非侵入性 适用于临床前概念验证研究的细胞调节方法 (NICR)。这项技术 可能用于治疗神经系统疾病，并提供一种侵入性较小的深脑替代方案 刺激（DBS）或光遗传学。因此，我们建议完善技术并开发原型设备 测试使用 NICR 治疗小鼠帕金森病 (PD) 症状。细胞活性为 由两个组件控制；自发形成 5 nm 铁的铁结合铁蛋白 纳米颗粒和 TRPV1，一种温度和机械敏感通道。通过将铁蛋白与 TRPV1 结合， 可以用射频 (RF)（加热或诱导铁蛋白的机械运动）或磁铁来控制通道 （引起运动）。该方法已被证明能够在体外和体内控制神经活动 体内，后者通过增加神经放电。此外，我们还向 TRPV1 引入了突变，可将 它进入氯离子通道，并且使用突变通道可以抑制神经活动 电磁波（例如 RF）。由于该系统是基因编码的，因此可以调节 重组腺苷酸将系统的两种蛋白质成分输送到细胞中 相关病毒（AAV）菌株。 AAV 已用于包括 PD 患者在内的众多人类研究。 因此，NICR 可以为植入电极 (DBS) 或植入光设备提供侵入性较小的替代方案 （光遗传学）用于调节神经活动（深部脑刺激），也可同时用于 控制神经回路中的多个不同节点。 在此申请中，我们提出了一组用于治疗 PD 的临床前概念验证研究 包括：1）完善技术以提高其效率并创建合适的 AAV 菌株 改善PD症状。我们还建议通过使用通道来提高系统的灵敏度 可以用较低的场强进行门控，并通过识别对铁蛋白具有增强敏感性的变体 电磁场； 2）开发能够产生局部电磁场的原型设备 适当的强度，目的是使该方法能够在常规实验室环境中使用，并最终作为 便携式/可穿戴设备； 3) 测试改进方法和合适仪器的能力 减轻小鼠PD症状； 4）创建具有cre依赖性表达的敲入小鼠 用于评估长期 TRPV1 和铁蛋白表达的安全性的构建体。该技术的验证 还可能导致其用于治疗神经系统内外部位的其他疾病 增加或减少细胞活性或调节蛋白质产生。最后，NICR的进一步发展 可以通过简单的交配来非侵入性地激活或抑制细胞，从而影响基础研究 转基因小鼠并将其暴露于射频或磁场中。

项目成果

The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity.

• DOI: 10.1016/j.neuron.2022.10.017
• 发表时间: 2022-11-02
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Martinez-Sanchez, Noelia;Sweeney, Owen;Sidarta-Oliveira, Davi;Caron, Alexandre;Stanley, Sarah A.;Domingos, Ana, I
• 通讯作者: Domingos, Ana, I