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.
