Chemogenetic Inactivation of the Primate Internal Globus Pallidus as a treatment for Parkinsonism

灵长类内部苍白球的化学遗传学灭活治疗帕金森病

• 批准号: 10577404
• 负责人: Adriana Galvan
• 金额: $ 45.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577404
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acetylcholine; Acute; Adverse effects; Affinity; Animal Model; Animals; Anions; Antiparkinson Agents; Autopsy; Basal Ganglia; Behavioral; Binding; Brain; Brain region; Cell Nucleus; Chronic; Clinical; Corpus striatum structure; Data; Devices; Dopamine; Dose; Electrons; Electrophysiology (science); FDA approved; Gliosis; Globus Pallidus; Glycine Receptors; Goals; Gold; Histologic; Infection; Ion Channel Gating; Ions; Lead; Levodopa; Ligand Binding Domain; Ligands; Light; Long-Term Effects; Longevity; MPTP Poisoning; Macaca mulatta; Mediating; Methods; Microscopic; Modeling; Monkeys; Motor; Motor Neurons; Movement; Mutate; National Institute of Neurological Disorders and Stroke; Neurons; Operative Surgical Procedures; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Pattern; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Primates; Specific qualifier value; Specificity; Surface; System; Techniques; Testing; Therapeutic; Translations; Viral; Viral Vector; Work; alpha-bungarotoxin receptor; awake; base; clinical practice; effective therapy; expectation; experimental study; extracellular; histological studies; human disease; minimally invasive; motor impairment; motor symptom; neuroinflammation; neuronal patterning; neurotoxic; nigrostriatal dopaminergic pathway; nonhuman primate; novel; novel strategies; parkinsonian non-human primate; receptor; receptor expression; response; side effect; smoking cessation; symptom treatment; treatment strategy; varenicline

PROJECT SUMMARY Parkinson’s disease (PD) leads to disabling motor impairments, resulting from the degeneration of the dopaminergic nigrostriatal pathway and a loss of dopamine in the striatum. These pathological changes alter the neuronal activity throughout the basal ganglia. One of the salient changes is that the activity in the motor portion of the internal pallidal segment (GPi) is increased and abnormally patterned. The currently available medication or neurosurgical treatments for the symptoms of PD are encumbered by unwanted side effects that frequently limit their use in patients. Many of the adverse effects of the current therapies undoubtedly result from their lack of cellular or brain circuit specificity. Minimally invasive methods to reversibly modulate neurons in a selective manner in the motor territory of the basal ganglia could provide an alternative approach to alleviate parkinsonism without side effects. We hypothesize that chemogenetic methods that target genetically specified neurons may be a safer, and at least equally effective alternative. Chemogenetic techniques involve the expression (through viral vectors) of artificial receptors in specific neurons. These receptors can then be activated by systemically administered compounds that are otherwise inert. In the planned experiments, we will use a novel chemogenetic approach, based on the expression of receptor-modulated ligand-gated ion channels, to reduce GPi activity in rhesus monkeys that have been rendered stably parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). The phenotypic and physiologic similarities between MPTP-induced parkinsonism and PD make the MPTP-treated monkey an excellent model for this purpose. We have strong preliminary results indicating that the chemogenetic receptors we plan to use (“Pharmacologically selective actuator molecules” (PSAMs)) can be successfully expressed in GPi neurons of monkeys using viral vectors, and that systemic administration of PSAM-activating compounds ameliorate GPi activity, with accompanying changes in movement. We now plan to evaluate the antiparkinsonian effects of PSAM-mediated inactivation of GPi in MPTP- treated monkeys (aim 1). In the course of these experiments, we will study the effects of acute or chronic administration of two PSAM-activating compounds (low doses of varenicline, a clinically approved smoking cessation drug, or a newly generated “pharmacologically selective effector molecule” (PSEM)). The responses to these drugs will be compared to those of the gold-standard antiparkinsonian medication, levodopa. Under aim 2, we will examine the pattern and longevity of the PSAM expression in the GPi and will histologically verify that chronic use of these chemogenetic therapeutic methods do not have identifiable neurotoxic effects. The proposed studies will help us to develop the PSAM approach into a treatment for parkinsonism, that could offer notable advantages over the currently available therapies.

项目摘要 帕金森氏病（PD）导致导致运动障碍，原因是 多巴胺能性黑质途径和纹状体中多巴胺的损失。这些病理变化改变了 整个巴萨神经节的神经元活性。显着变化之一是电机部分的活动 内部颗粒段（GPI）的增加并具有绝对图案。当前可用的药物 或神经外科治疗PD症状的因素，经常受到不必要的副作用的影响 限制他们在患者中的使用。当前疗法的许多不良影响无疑是由于缺乏 细胞或脑电路特异性的特异性。在选择性中可逆地调节神经元的最小侵入性方法 巴萨神经节的汽车领域的方式可以提供一种减轻帕金森主义的替代方法 没有副作用。我们假设靶向遗传指定神经元的化学发生方法可能 成为更安全，至少同样有效的替代方案。化学发生技术涉及表达（通过 特定神经元中人造受体的病毒载体。然后可以通过系统地激活这些受体 施用否则惰性的化合物。在计划的实验中，我们将使用一种新型的化学生成 基于接收器调节的配体门控离子通道的表达，以减少GPI活性 通过用1-甲基-4-苯基-1,2,3,6-进行处理，恒河猴的恒河猴猴 四氢吡啶（MPTP）。 MPTP诱导的帕金森主义之间的表型和生理相似性 PD使经MPTP处理的猴子成为了此目的的绝佳模型。我们有很强的初步结果 表明我们计划使用的化学遗传受体（“药理学选择性执行器分子” （PSAMS））可以使用病毒载体成功地在猴子的GPI神经元中表达 施用PSAM激活化合物可以改善GPI活性，参与变化 移动。现在，我们计划评估PSAM介导的GPI在MPTP-中失活的抗帕金森氏菌作用。 处理过的猴子（AIM 1）。在这些实验过程中，我们将研究急性或慢性的影响 给药两种PSAM激活化合物（低剂量的Varenicline，临床批准的吸烟 停止药物或新生成的“药理学选择性效应分子”（PSEM））。回答 将这些药物与金色标准的Antiparkinsinian药物左旋多巴进行比较。在目标下 2，我们将检查GPI中PSAM表达的模式和寿命，并将在组织学上验证 这些化学发生治疗方法的长期使用没有可识别的神经毒性作用。这 拟议的研究将帮助我们开发PSAM方法来治疗帕金森氏症，可以提供 与当前可用的疗法相比，有明显的优势。