# Pre-Clinical Evaluation of a Rationally Designed Nanotherapeutic for Huntington's Disease

> **NIH NIH R43** · NEURANO BIOSCIENCE · 2021 · $518,505

## Abstract

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.

## Key facts

- **NIH application ID:** 10258489
- **Project number:** 1R43NS122666-01
- **Recipient organization:** NEURANO BIOSCIENCE
- **Principal Investigator:** ELENA MOLOKANOVA
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $518,505
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258489

## Citation

> US National Institutes of Health, RePORTER application 10258489, Pre-Clinical Evaluation of a Rationally Designed Nanotherapeutic for Huntington's Disease (1R43NS122666-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10258489. Licensed CC0.

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