Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY Major depressive disorder (MDD) is a debilitating psychiatric disorder with a high lifetime prevalence, imposing a severe economic burden on society. Despite a number of clinically effective treatments for MDD, many patients exhibit resistance to current antidepressants. Thus, novel interventions based on pathological mechanisms of MDD are needed. We recently discovered that glutaminase (GLS1), the enzyme which catalyzes the hydrolysis of glutamine to glutamate, is highly upregulated in activated microglia in the brain of mice subject to Chronic Social Defeat Stress (CSDS), a well-established rodent model used to study stress-induced mood disorders, including depression. We then reported that inhibiting the elevated glutaminase activity with JHU083, a glutamine analog prodrug, dramatically inhibited the stress-induced microglial glutaminase upregulation, inflammatory cytokine induction, and normalized the CSDS-induced social avoidance and anhedonia. Although JHU083 showed therapeutic efficacy, its translational potential is hampered by its propensity to cause gastrointestinal toxicity likely associated with its reactive diazo group and its non-selective inhibition of all glutamine-utilizing enzymes, not just GLS1. Given the significant clinical potential of this mechanism, we propose to overcome this limitation by utilizing our recently developed selective GLS1 inhibitor JHU29 and directly targeting microglial GLS1 by attaching JHU29 to hydroxyl-dendrimer nanoparticles delivery system. Our team discovered that hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers (~4-10 nm) selectively target activated microglia in the injured brain while showing minimal uptake in healthy brains. This is a highly translational approach, as targeted dendrimer delivery has been demonstrated to be well-tolerated and efficacious in multiple large and small animal models and was recently shown efficacy in a Ph2 clinical trial (NCT04458298). We have assembled a highly experienced team with extensive expertise in neuroinflammatory mechanisms and preclinical models of chronic stress (Zhu), dendrimer nanoparticles (Rangaramanujam), pharmacokinetics (Rais), glutaminase drug discovery and clinical translation (Slusher). Together we will develop a dendrimer-glutaminase inhibitor conjugate (Dendrimer-JHU29) for chronic stress-associated psychosocial behavior deficits by implementing the following three aims: AIM 1- Synthesize and characterize generation-4 (G4) and generation-6 (G6) Dendrimer- JHU29 conjugates. AIM 2- Assess their oral pharmacokinetics, microglial target engagement, tolerability, and biodistribution. AIM 3- Using the optimal conjugate and dosing paradigm from Aim 2, evaluate its therapeutic and tolerability profile in CSDS and vicarious defeat stress (VDS) mice models. Successful execution of these aims will result in a Dendrimer-JHU29 conjugate ready for Investigational New Drug (IND)-enabling studies to support future clinical studies to combat chronic stress-associated depression.
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