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

基本信息

批准号：
10710400
负责人：
Adriana Galvan
金额：
$ 45.5万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10710400
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acetylcholine Acute Adverse effects Affect Affinity Animal Model Animals Anions Autopsy Basal Ganglia Behavioral Binding Brain Brain region Cell Nucleus Chronic Clinical Corpus striatum structure Data Devices Dopamine Dose Electrons Electrophysiology (science)FDA approved Genetic Genetic Techniques Gliosis Globus Pallidus Glycine Receptors Goals Histologic Infection Ion Channel Gating Ions 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 Pharmacotherapy Phenotype Physiological Predisposition Primates Specific qualifier value Specificity Surface System Techniques Testing Therapeutic Translations Viral Viral Vector Work alpha-bungarotoxin receptor awake clinical practice expectation experimental study extracellular genetic approach histological studies human disease minimally invasive motor impairment motor symptom neuroinflammation neuronal patterning neurosurgery neurotoxic nigrostriatal dopaminergic pathway nonhuman primate novel novel strategies parkinsonian non-human primate pharmacologic receptor receptor expression response side effect smoking cessation symptom treatment treatment strategy varenicline

项目摘要

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.

项目概要帕金森病 (PD) 会因大脑退化而导致运动障碍这些病理变化改变了纹状体中的多巴胺能黑质纹状体通路和多巴胺的损失。整个基底神经节的神经活动的显着变化之一是运动部分的活动。内部苍白球段 (GPi) 增加且形态异常目前可用的药物。针对 PD 症状的神经外科或神经外科治疗常常会受到不良副作用的阻碍限制它们在患者中的使用无疑是由于它们的缺乏造成的。细胞或脑回路特异性的微创方法可逆地调节神经元。基底神经节运动区的方式可以提供缓解帕金森症的替代方法我们追求的是针对基因特定神经元的化学遗传学方法。是一种更安全、至少同样有效的替代方案，涉及表达（通过）。然后可以通过系统性激活特定神经元中的人工受体（病毒载体）。在计划的实验中，我们将使用一种新的化学遗传学。方法，基于受体调节的配体门控离子通道的表达，以降低 GPi 活性通过 1-甲基-4-苯基-1,2,3,6- 治疗使帕金森病稳定的恒河猴四氢吡啶 (MPTP) MPTP 诱导的帕金森症之间的表型和生理相似性。和 PD 使 MPTP 治疗的猴子成为实现此目的的优秀模型。我们已经取得了强有力的初步结果。表明我们计划使用的化学遗传受体（“药理学选择性致动分子” (PSAM))可以使用病毒载体在猴子的GPi神经元中成功表达，并且系统性施用 PSAM 激活化合物可改善 GPi 活性，并伴随变化我们现在计划评估 MPTP 中 PSAM 介导的 GPi 失活的抗帕金森病作用。猴子（目标 1）在这些实验过程中，我们将研究急性或慢性的影响。给予两种 PSAM 激活化合物（低剂量伐尼克兰，一种临床批准的吸烟药物）戒烟药物，或新产生的“药理学选择性效应分子”（PSEM））。这些药物将与金标准抗帕金森病药物左旋多巴进行比较。 2，我们将检查 GPi 中 PSAM 表达的模式和寿命，并通过组织学验证长期使用这些化学遗传学治疗方法不会产生可识别的神经毒性作用。拟议的研究将帮助我们将 PSAM 方法开发为帕金森病的治疗方法，这可以提供与目前可用的疗法相比具有显着的优势。