Circuit-specific, chemogenetic neuromodulation in nonhuman primates. - 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.
