Project Summary for Novel, Orally-available Prodrugs for Alzheimer's Disease Dr. Colton at Duke University Medical Center was among the first to publish that early stages of Alzheimer's disease were characterized by an immuno-suppressive condition in the brain (Colton et al. 2006a). As the disease progresses, an immuno-toxic condition is acquired with disease progression so that at post- mortem analysis, both pro-inflammatory and anti-inflammatory immune mediators are present. In an elegant reduction to practice, Kan et al. (2015) used difluoromethylornithine (DFMO) to show that reduction of immuno- suppressive polyamines resulted in significantly improved learning and memory behavior and reduced Abeta 1- 40 and 1-42 in the CVN-AD mouse model of AD. Town's laboratory (Guillot-Sestier et al. 2015) and Chakrabaty et al. (2015) showed that increasing immuno-suppressive activities was associated with enhanced amyloid plaque formation and worsening cognitive behavior, while removing immuno-suppressive activities appears to mitigate these Alzheimer's-like pathologies. These and other publications provide strong support for the idea that reducing immuno-suppression may be a new and effective therapeutic approach to Alzheimer's disease reduction. Polyamines are immuno-suppressive mediators and polyamine levels increase in AD brains. DFMO is a potent, orally-available irreversible inhibitor of the key enzyme required for polyamine synthesis, Ornithine DeCarboxylase (ODC). Thus, our treatment thesis is to reduce brain polyamine levels to reduce brain immuno-suppression and inhibit and/or stop the development of disease when treatment is initiated at early stages of AD. DFMO is an FDA-approved drug for the treatment of sleeping sickness due to parasitic infection of the brain that is off-patent and no longer marketed, making commercialization a challenge. We have solved this problem by creating novel prodrugs of DFMO that reduce polyamine levels, are orally-available, may not have the same undesirable side-effect profile as DFMO-alone, and are patent-pending (Tavares and Vitek, WO 2016/168118 A1). In Phase 1, we successfully created DFMO-prodrugs and characterized them in vitro. In Phase 2, we are proposing to continue development of DFMO-prodrugs by making additional prodrugs, characterizing them in vitro and in vivo, determining whole animal pharmacokinetic and pharmacodynamic profiles, and testing them in the CVN-AD mouse model. These additional activites are laying the groundwork for selection of a lead and a backup compound, an important milestone on the critical-path that will be taken into clinical development of Resilio's DFMO-prodrugs for an Alzheimer's indication.