PROJECT SUMMARY Huntington’s disease (HD) is an inherited CAG-polyglutamine repeat expansion neurodegenerative disorder characterized by cognitive and psychiatric impairment. HD is associated with synaptic dysfunction and neuronal loss in the corticostriatal system of the brain. In HD, increased susceptibility of neurons to glutamatergic excitotoxicity has been linked to activation of extrasynaptic NMDA receptors (eNMDARs) located outside synapses. Several studies have used NMDA receptor antagonists to interrupt this cellular pathology, but NMDAR antagonists also produce side effects due to disruption of physiological synaptic communication. Memantine, an NMDAR antagonist with preferential inhibition toward eNMDARs, has been tested in several studies, but produced unsatisfactory results due to a narrow window of efficacy versus toxicity. To circumvent this problem, we recently developed a first-in-class exclusive antagonist of eNMDARs by attaching memantine via polymer linkers to a gold (Au) nanoparticle, so that the resulting gold-memantine (AuM) nanotherapeutic is too large to gain access to the synaptic cleft, and thus is restricted to extrasynaptic regions where it will preferentially inhibit eNMDARs. Our preliminary studies of AuM demonstrate that AuM achieves potent neuroprotection in primary neuron models of HD, ischemic stroke, and Alzheimer’s disease, and we validated intracerebroventricular injection of AuM as a viable in vivo therapy in a pilot preclinical trial in BAC-HD mice. Based upon these exciting results, we propose to evaluate AuM as a treatment for HD. In Phase I, we will validate the utility of AuM as a therapy for HD by producing AuM in sufficient quantity and potency, by confirming AuM action against eNMDAR toxicity in primary neuron models of HD, and by establishing proof-of-concept efficacy of AuM in a pilot study in HD mice. If we achieve a set of objectives, quantitative milestones, we will proceed to Phase II, where we will complete pharmacokinetics and pharmacodynamics studies to ascertain the optimal AuM dosage and administration routes for a preclinical trial of AuM in HD N171-82Q mice. The ultimate goal of this project will be to determine if AuM is capable of significant neuroprotection in HD mice and patient neurons, and thus should be considered for further development as a drug treatment for human HD.