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