Circuit-specific, chemogenetic neuromodulation in nonhuman primates.

非人类灵长类动物的电路特异性化学遗传学神经调节。

• 批准号: 10651371
• 负责人: SERGE E PRZEDBORSKI
• 金额: $ 155.05万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651371
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Agonist; Anatomy; Area; Autopsy; Behavior; Behavior assessment; Behavioral; Benserazide; Bilateral; Biological Markers; Blinded; Brain; Chorea; Chronic; Clinical; Cognition; Combined Modality Therapy; Corpus striatum structure; Deep Brain Stimulation; Dependovirus; Disease; Dissection; Dopamine; Dose; Effectiveness; Enterobacteria phage P1 Cre recombinase; Euthanasia; Evaluation; Female; Focused Ultrasound; Future; Genetic; Globus Pallidus; Goals; Histologic; Histology; Human; Individual; Infection; Inflammatory; Injections; Levodopa; Ligands; MPTP non-human primate; Mechanics; Mental disorders; Methods; Monitor; Monkeys; Motor; Mus; Neurologic; Neurons; Neurotoxins; Operative Surgical Procedures; Oral; Oral Administration; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Phase; Positron-Emission Tomography; Regimen; Reproducibility; Research; Research Personnel; Safety; Side; Sonication; Structure of subthalamic nucleus; Testing; Tissues; Translating; Translations; Universities; Validation; Viral; Viral Vector; Work; behavioral response; brain pathway; density; designer receptors exclusively activated by designer drugs; dosage; drug distribution; experimental study; fluorodeoxyglucose positron emission tomography; follow-up; gene therapy; improved; in vivo; indexing; male; motor symptom; neuropathology; neuroregulation; nonhuman primate; novel; parkinsonian non-human primate; preclinical trial; receptor; receptor expression; side effect; standard care; success; surgical risk; tool; tool development; translation to humans; vector

ABSTRACT ‒ UG3/UH3 Deep Brain Stimulation (DBS), applied to areas like the subthalamic nucleus (STN), is a standard treatment for Parkinson Disease (PD), however, DBS has inherent surgical risks as well as potential for infections and adverse side effects. Our overarching goal is to establish novel chemogenetic neuromodulation strategies in nonhuman primates (NHPs) that utilize and build upon the strengths of DBS but resolve many DBS limitations, and ultimately to translate these to clinical therapies in humans. We focus on Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), which work via specialized excitatory or inhibitory receptors genetically inserted into neurons. Our Research Plan, which integrates a robust Plan to Enhance Diverse Perspectives, has a tool development (UG3) phase followed by a pre-clinical trial (UH3) phase. The main objective of the UG3 is to: a) develop more effective and specific DREADD induction in NHPs: a) using a circuit-specific retro-infection method to selectively infect the neurons comprising STN→GP pathway, believed to be key to motor symptoms in PD, and b) use focused ultrasound prior to surgical delivery of viral constructs to augment DREAD expression in the STN→GP circuit. We will use positron emission tomography (PET) and behavioral assessments to gauge the strength of viable DREADD receptor expression, and post-mortem histology to screen for neuropathology and to assess the density and anatomical distribution of transduced neurons. The go/no-go for decision for moving to the UH3 will be based on: 1) Evidence of motor abnormalities or behavioral change due to DREADD activation with an effect size ≥0.80, and/or 2) histological evidence of DREADD expression in ≥35% of neurons in the STN. The main objective of the UH3 is to determine if activation of DREADDs in STN neurons, using the oral DREADD agonist deschloroclozapine (DCZ), reduces motor abnormalities NHPs treated with a neurotoxin to induce a PD-like condition. We will start (AIM 1) by determining the optimal oral agonist dosage and efficacy for DREADD activation in MPTP NHPs. We will then (AIM 2) determine the long-term efficacy and safety of oral DREADD activation in MPTP NHPs, with clinical/behavioral analyses emphasizing clinical benefits, and motor/non-motor side effects. We will use PET in the same NHPs to monitor the stability of DREADD effects on STN circuits and follow up with histological analysis to confirm DREADD distribution across STN circuits, to look for potential tissue damage and to confirm striatal dopamine depletion due to the neurotoxin treatment. Finally (AIM 3) we will explore the use of PET in the same NHPs as a noninvasive a gauge for the efficacy of the DREADD agonist alone or as part of a combined therapy to guide dosage adjustment in future human studies. To enhance the rigor and reproducibility, key UH3 experiments will be independently validated. Success in this work and its human translation may be game-changing for the treatment of PD and other neurological/psychiatric disorders.

摘要 – UG3/UH3 深部脑刺激 (DBS) 应用于丘脑底核 (STN) 等区域，是一种标准治疗方法 然而，帕金森病（PD）DBS 具有固有的手术风险以及感染和潜在风险。 我们的首要目标是建立新的化学遗传学神经调节策略。 非人类灵长类动物 (NHP) 利用 DBS 的优势并以此为基础，但解决了 DBS 的许多局限性， 并最终将这些转化为人类的临床疗法，我们只专注于设计受体。 由设计药物 (DREADD) 激活，通过专门的兴奋性或抑制性受体发挥作用 我们的研究计划整合了一个强大的增强多样性计划。 展望，有一个工具开发（UG3）阶段，然后是临床前试验（UH3）阶段。 UG3 的目标是： a) 在 NHP 中开发更有效和更具体的 DREADD 诱导： a) 使用 电路特异性逆向感染方法选择性感染包含 STN→GP 通路的神经元，认为 是帕金森病运动症状的关键，并且 b) 在手术递送病毒构建体之前使用聚焦超声 为了增强 STN→GP 电路中的 DREAD 表达，我们将使用正电子发射断层扫描 (PET) 和 行为评估，以衡量可行的 DREADD 受体表达的强度，以及尸检 组织学筛查神经病理学并评估转导的密度和解剖分布 决定是否转移到 UH3 将基于：1) 运动证据。 由于 DREADD 激活而导致的异常或行为变化，效应大小≥0.80，和/或 2) 组织学 STN 中 ≥35% 的神经元中存在 DREADD 表达的证据 UH3 的主要目标是 使用口服 DREADD 激动剂去氯氯氮平确定 STN 神经元中的 DREADD 是否被激活 (DCZ) 减少运动异常 NHP 用神经毒素治疗可诱导 PD 样病症。 (AIM 1) 通过确定 MPTP NHP 中 DREADD 激活的最佳口服激动剂剂量和功效。 然后，我们将（目标 2）确定口服 DREADD 激活在 MPTP NHP 中的长期功效和安全性， 我们将使用强调临床益处和运动/非运动副作用的临床/行为分析。 PET 在相同的 NHP 中监测 DREADD 对 STN 电路的影响的稳定性并跟进 组织学分析以确认 DREADD 在 STN 回路中的分布，以寻找潜在的组织损伤 并确认神经毒素治疗导致的纹状体多巴胺耗竭。最后（AIM 3）我们将探讨。 在相同的 NHP 中使用 PET 作为非侵入性指标来衡量 DREADD 激动剂单独或作为 DREADD 激动剂的功效 联合治疗的一部分，用于指导未来人体研究的剂量调整，以提高严谨性和有效性。 重复性，关键的 UH3 实验将得到独立验证。 翻译可能会改变帕金森病和其他神经/精神疾病的治疗游戏规则。