UG3MH129381

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's disease (PD). However, DBS carries inherent surgical risks, 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 while resolving many of its limitations. Ultimately, we aim to translate these strategies into clinical therapies for 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 consists of a tool development (UG3) phase followed by a pre-clinical trial (UH3) phase, integrating a robust plan to enhance diverse perspectives.

The main objective of the UG3 phase 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 the STN-GP pathway, believed to be key to motor symptoms in PD.
b) Use focused ultrasound prior to surgical delivery of viral constructs to augment DREADD 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. Post-mortem histology will be conducted to screen for neuropathology and assess the density and anatomical distribution of transduced neurons.

The go/no-go decision for moving to the UH3 phase will be based on:
1) Evidence of motor abnormalities or behavioral change due to DREADD activation with an effect size = 0.80.
2) Histological evidence of DREADD expression in ≥ 35% of neurons in the STN.

The main objective of the UH3 phase is to determine if activation of DREADDs in STN neurons, using the oral DREADD agonist deschloroclozapine (DCZ), reduces motor abnormalities in 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. Then, we will (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. PET will be used in the same NHPS to monitor the stability of DREADD effects on STN circuits. Histochemical analysis will confirm DREADD distribution across STN circuits, look for potential tissue damage, and 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 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 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.

Research Foundation For Mental Hygiene

NOT APPLICABLE

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Orangeburg, New York 109621159 United States

Single Zip Code

BRAIN Initiative: Development of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in Human and Non-Human Primate Brain (UG3/UH3 Clinical Trial Optional) (RFA-MH-22-115)

Amendment Since initial award the total obligations have increased 71% from $1,550,458 to $2,658,871.