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.

项目摘要 在此协作和跨学科应用中，我们建议进一步发展一种新颖的非侵入性 细胞调节方法（NICR），适用于临床前概念证明。这项技术 可能可用于治疗神经疾病，并为深脑的侵入性替代品提供不足的替代品 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NICR用于治疗小鼠帕金森氏病（PD）症状的治疗。细胞活动是 由两个组件控制；自发形成5 nm铁的铁结合铁蛋白蛋白 纳米颗粒和TRPV1，温度和机械敏感的通道。通过将铁蛋白绑在TRPV1上，一个 可以用射频（RF）（热或诱导铁蛋白的机械运动）或磁铁隔离通道 （引起运动）。该方法已被证明能够在体外和IN中控制神经活动 Vivo，后者通过增加神经射击。此外，我们已经在TRPV1中引入了一个突变，以转换 它进入氯化物通道，使用突变通道的使用使使用神经活动 电磁波（例如RF）。由于系统是遗传编码的，因此可以调节 重组腺体已输送了系统的两个蛋白质成分的细胞 相关病毒（AAV）菌株。 AAV已用于包括PD患者在内的许多人类研究中。 因此，NICR可以提供植入电极（DB）或植入轻型设备的侵入性较低的替代品 （光遗传学）用于调节神经活动（深脑刺激），也用于同时使用 控制神经回路中的几个不同节点。 在此应用中，我们提出了一组临床前概念验证研究，以治疗PD 包括：1）提高其效率并创造合适的AAV菌株的技术的改进 改善PD的症状。我们还建议通过使用通道来提高系统的灵敏度 可以通过较低的场强度和识别铁蛋白的变体以增强对一个 电磁场； 2）开发原型设备，该原型设备将创建局部电磁场 合适的力量，目的是使该方法在常规实验室环境中使用，最终 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的症状； 4）创建具有CRE依赖性表达的敲击蛋白小鼠 评估长期TRPV1和铁蛋白表达的安全性的构造。该技术的验证 也可能导致其用于治疗神经系统内外部位的其他疾病的治疗 增加或降低细胞活性或调节蛋白质产生。最后，NICR的进一步发展 通过简单地交配，可以通过允许非侵入性激活或抑制细胞来影响基础研究 基因修饰的小鼠并将其暴露于RF或磁场。

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