Huntington's disease (HD) is an inherited CAG-polyglutamine repeat expansion neurodegenerative disordercharacterized by cognitive and psychiatric impairment. HD is associated with synaptic dysfunction and neuronalloss in the corticostriatal system of the brain. In HD, increased susceptibility of neurons to glutamatergicexcitotoxicity has been linked to activation of extrasynaptic NMDA receptors (eNMDARs) located outsidesynapses. Several studies have used NMDA receptor antagonists to interrupt this cellular pathology, butNMDAR 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 severalstudies, but produced unsatisfactory results due to a narrow window of efficacy versus toxicity. To circumventthis problem, we recently developed a first-in-class exclusive antagonist of eNMDARs by attaching memantinevia polymer linkers to a gold (Au) nanoparticle, so that the resulting gold-memantine (AuM) nanotherapeutic istoo large to gain access to the synaptic cleft, and thus is restricted to extrasynaptic regions where it willpreferentially inhibit eNMDARs. Our preliminary studies of AuM demonstrate that AuM achieves potentneuroprotection in primary neuron models of HD, ischemic stroke, and Alzheimer's disease, and we validatedintracerebroventricular 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 willvalidate the utility of AuM as a therapy for HD by producing AuM in sufficient quantity and potency, by confirmingAuM action against eNMDAR toxicity in primary neuron models of HD, and by establishing proof-of-conceptefficacy of AuM in a pilot study in HD mice. If we achieve a set of objectives, quantitative milestones, we willproceed to Phase II, where we will complete pharmacokinetics and pharmacodynamics studies to ascertain theoptimal AuM dosage and administration routes for a preclinical trial of AuM in HD N171-82Q mice. The ultimategoal of this project will be to determine if AuM is capable of significant neuroprotection in HD mice and patientneurons, and thus should be considered for further development as a drug treatment for human HD.
Public Health Relevance Statement: PROJECT NARRATIVE
In Huntington's disease (HD), neurotoxicity mediated by extrasynaptic NMDA receptors has been shown to
play a critical role in neuronal death, but while NMDA receptor antagonists, such as memantine, can interrupt
this cellular pathology, NMDAR antagonists also produce side effects due to disruption of physiological
synaptic communication. Using a rational design approach, we have developed a first-in-class exclusive
antagonist of extrasynaptic NMDA receptors by attaching memantine via polymer linkers to a gold (Au)
nanoparticle, so that the resulting nanotherapeutic is too large to gain access to the synaptic cleft, and we
have documented that AuM achieves potent neuroprotection against NMDAR-mediated cytotoxicity both ex
vivo in primary neuron models and in vivo in mice. Here we propose to evaluate AuM in a Phase I proposal,
where we will first demonstrate synthesis of bioactive AuM and determine if AuM is capable of
physiologically relevant neuroprotection in a pilot study in HD transgenic mice.
Project Terms: Production ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; Role ; social role ; Synapses ; Synaptic ; synapse ; Testing ; Work ; Dopamine D2 Receptor ; D2 receptor ; DRD2 Receptor ; N-Methylaspartate ; N Methyl D aspartic Acid ; N methyl D aspartate ; N-Methyl-D-aspartate ; NMDA ; N-Methyl-D-Aspartate Receptors ; N-Methylaspartate Receptors ; NMDA Receptor-Ionophore Complex ; NMDA Receptors ; Mediating ; Brain-Derived Neurotrophic Factor ; BDNF ; Guidelines ; analytical method ; base ; dosage ; Phase ; Physiological ; Physiologic ; Neurologic ; Neurological ; Link ; Predisposition ; Susceptibility ; insight ; Hand Strength ; Grip strength ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Therapeutic ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Poly Q ; polyQ ; polyglutamine ; Involuntary Movements ; Hereditary ; Inherited ; Route ; System ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; Expanded Trinucleotide Repeat ; Trinucleotide Repeat Expansion ; cellular pathology ; Lytotoxicity ; cytotoxicity ; NMDA receptor antagonist ; nerve cell death ; nerve cell loss ; neuron cell death ; neuron cell loss ; neuron death ; neuronal cell death ; neuronal cell loss ; neuronal death ; neuronal loss ; neuron loss ; neuroprotection ; cohort ; transgenic ; Transgenic Organisms ; Toxicities ; Toxic effect ; novel ; Synaptic Cleft ; Pathogenesis ; Coding System ; Code ; Modeling ; Property ; HD Gene ; Huntingtin ; IT15 gene ; interesting transcript 15 ; Huntington gene ; Huntingtin Protein ; Huntington's disease gene product ; Huntington protein ; Brain Trauma ; traumatic brain damage ; Traumatic Brain Injury ; neuropathology ; BAC clone ; BACs ; Bacterial Artificial Chromosomes ; Ischemic Stroke ; Pathogenicity ; protein expression ; preventing ; prevent ; Interruption ; Motor ; in vitro Assay ; in vivo ; in vivo Model ; Cognitive ; Validation ; Preparation ; Molecular ; Development ; developmental ; Image ; imaging ; National Institute of Neurological Disorders and Stroke ; NINDS ; National Institute of Neurological Diseases and Stroke ; disease phenotype ; design ; designing ; CAG repeat ; CAG trinucleotide repeat ; nanotherapeutic ; nano therapeutic ; excitotoxicity ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Outcome ; Impairment ; neurotoxicity ; neuron toxicity ; neuronal toxicity ; synaptic inhibition ; synapse inhibition ; mitochondrial dysfunction ; stem ; therapy development ; develop therapy ; intervention development ; treatment development ; FDA approved ; preclinical evaluation ; pre-clinical evaluation ; preclinical efficacy ; pre-clinical efficacy ; preclinical trial ; pre-clinical trial ; efficacy study ; Injections ; preservation ; side effect ; pharmacokinetics and pharmacodynamics ; PK/PD ; efficacious treatment ; efficacious therapy ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Mental disorders ; Mental health disorders ; Psychiatric Disease ; Psychiatric Disorder ; mental illness ; psychiatric illness ; psychological disorder ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain ; Brain Nervous System ; Encephalon ; Calcium ; Cell Death ; necrocytosis ; Clinical Trials ; Communication ; Corpus striatum structure ; Corpus Striatum ; Striate Body ; Striatum ; striatal ; Disease ; Disorder ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Electrophysiology (science) ; Electrophysiology ; Neurophysiology / Electrophysiology ; electrophysiological ; Genes ; Glutamates ; L-Glutamate ; glutamatergic ; Goals ; Gold ; Health ; Human ; Modern Man ; Huntington Disease ; Huntington Chorea ; Huntington's ; Huntington's Disease ; Huntington's Disease Pathway ; Huntingtons Disease ; In Vitro ; Longevity ; Length of Life ; life span ; lifespan ; Memantine ; Memantin ; Transgenic Mice ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Patients ; Pharmacology ; Pilot Projects ; pilot study ; Play ; Polymers ;
