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Principal Investigator: Ahmet Hoke
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $580,168
Funding agency: National Institute on Aging
PROJECT SUMMARY
Age-related loss of muscle mass, or sarcopenia, is a hallmark of aging that affects up to 20% of those over 65
and up to 50% of those over 80, for which there are no pharmacological treatments. We recently discovered that
the enzyme Glutamate Carboxypeptidase II (GCPII), which catalyzes the hydrolysis of N-acetylaspartylglutamate
(NAAG) to glutamate, is highly upregulated in activated macrophages infiltrating muscle during aging, and that
inhibiting the elevated GCPII activity with the inhibitor 2-PMPA (IC50 = 0.3nM) dramatically delays neuromuscular
junction (NMJ) denervation, and muscle function and volume loss. Unfortunately, 2-PMPA is not clinically
developable. It is highly polar, with negligible oral bioavailability (F<2%), a short half-life (<30m), and is active
only with high systemic (IP) doses. Given its significant clinical potential, we propose to address these limitations
by utilizing hydroxyl-dendrimers to facilitate its sustained and targeted delivery. Hydroxyl-dendrimers have shown
promise as targeted delivery systems due to their size (~4-10 nm) and surface attributes. They are rapidly cleared
from circulation under normal conditions but are selectively engulfed and retained by activated and phagocytic
immune cells under injury or inflammatory conditions. This is a very translational approach, as targeted
dendrimer delivery has been demonstrated to be efficacious in multiple animal models and recently shown to
reduce inflammation and mortality in a Ph2 clinical trial in hospitalized patients with severe Covid-19
(NCT04458298). We have assembled a highly experienced team with extensive expertise in neuromuscular
disorders and aging (Hoke), dendrimer nanoparticles (Kannan), and animal pharmacology, pharmacokinetics,
and clinical translation (Slusher). Together we plan to develop dendrimer-2PMPA (D-2PMPA) for age-related
sarcopenia by implementing the following aims: AIM 1. Synthesize and characterize generation 4 (G4) and
generation 6 (G6) D-2PMPA conjugates. AIM 2. Assess D-2PMPA (G4 and G6) pharmacokinetics, target
engagement, and biodistribution in aged mice. AIM 3. Evaluate the efficacy (behavioral, electrophysiological,
and histological) and tolerability of the selected D-2PMPA conjugate in aged mice. Successful execution of these
aims will result in a D-2PMPA conjugate ready for IND-enabling studies to support future clinical studies to
combat age-related sarcopenia.
Terms: <21+ years old><Acids><Address><Adult><Adult Human><Affect><Aging><Animal Model><Animal Models and Related Studies><Animals><Assay><Autopsy><Behavioral><Bioassay><Bioavailability><Biodistribution><Biological Assay><Biological Availability><Blood Plasma><Body Tissues><Body Weight><Cell Body><Cells><Charge><Chronic><Circulation><Clinical><Clinical Chemistry><Clinical Research><Clinical Study><Clinical Trials><Cy5><Dendrimers><Dendritic Compounds><Dendrons><Denervation><Development><Diameter><Disease><Disorder><Dose><Drug Kinetics><Drugs><Economic Burden><Electromyography><Electrophysiology><Electrophysiology (science)><Enzyme Gene><Enzymes><FOLH><FOLH1><FOLH1 gene><Fiber><Folate Hydrolase 1><Fracture><Future><GCP2><Generations><Glutamate Carboxypeptidase II><Glutamates><Grip strength><Half-Life><Hand Strength><Health Care Costs><Health Costs><Healthcare Costs><Histologic><Histologically><Hortega cell><Hospital Admission><Hospitalization><Human><Hydrolysis><Hydroxyl><Hydroxyl Radical><Immune><Immunes><Infiltration><Inflammation><Inflammatory><Injury><Kinetics><L-Glutamate><Label><Link><Liquid substance><Locomotion><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Maintenance><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mice><Mice Mammals><Microglia><Modern Man><Murine><Mus><Muscle><Muscle Tissue><Muscle function><Myoneural Junction><Mφ><N-Acetylated Alpha-Linked Acidic Dipeptidase 1><N-acetyl-1-Asp-Glu><N-acetyl-aspartyl-glutamate><N-acetylaspartylglutamate><NAALAD1><NAALADase I><NMR Imaging><NMR Tomography><Nerve Transmitter Substances><Neuromuscular Diseases><Neuromuscular Junction><Neuropeptides><Neurophysiology / Electrophysiology><Neurotransmitters><Nuclear Magnetic Resonance Imaging><Oral><PSM><PSMA><Pathologic><Patients><Penetration><Phagocytes><Phagocytic Cell><Pharmaceutical Preparations><Pharmacokinetics><Pharmacological Treatment><Pharmacology><Physical Function><Physiologic><Physiologic Availability><Physiological><Plasma><Plasma Serum><Population><Prevention><Process><Prostate-Specific Membrane Antigen><Reticuloendothelial System, Serum, Plasma><Risk><Source><Staining method><Stains><Stomach><Surface><System><Testing><Tissues><Transmission><Weight><Zeugmatography><adulthood><age associated><age associated muscle atrophy><age correlated><age dependent><age linked><age related><age specific><age-associated decline in muscle><age-associated muscle decline><age-associated muscle deterioration><age-associated muscle loss><age-associated muscle wasting><age-related decline in muscle><age-related muscle decline><age-related muscle deterioration><age-related muscle loss><age-related muscle wasting><aged mice><aged mouse><aged muscle><aging of muscle><amebocyte><bone fracture><clinical translation><clinically translatable><combat><cyanine dye 5><determine efficacy><developmental><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elderly mice><electrophysiological><evaluate efficacy><examine efficacy><experience><falls><fluid><fracture risk><gastric><gitter cell><glutamate signaling><glutamatergic><glutamatergic dendrodendritic synapses><glutamatergic signaling><hallmarks of aging><in vivo><inhibitor><injuries><innervation><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><liquid><mesoglia><microglial cell><microgliocyte><model of animal><mortality><muscle aging><muscle bulk><muscle form><muscle mass><muscular><myoneural disorder><nano particle><nano-sized particle><nanoparticle><nanosized particle><necropsy><nerve supply><neuromuscular degenerative disorder><neuromuscular disorder><old mice><perivascular glial cell><pillars of aging><postmortem><sarcopenia><sarcopenic><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><site targeted delivery><small molecule><targeted delivery><translation strategy><translational approach><translational strategy><transmission process><weights>