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.