Novel, Orally-Available Prodrugs for Alzheimer's Disease

Project Summary for NovelOrally available Prodrugs for Alzheimer s DiseaseDrColton 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 brainColton et alaAs the disease progressesan immuno toxic condition is acquired with disease progression so that at postmortem analysisboth pro inflammatory and anti inflammatory immune mediators are presentIn an elegant reduction to practiceKan et alused difluoromethylornithineDFMOto show that reduction of immunosuppressive polyamines resulted in significantly improved learning and memory behavior and reduced Abetaandin the CVN AD mouse model of ADTown s laboratoryGuillot Sestier et aland Chakrabaty et alshowed that increasing immuno suppressive activities was associated with enhanced amyloid plaque formation and worsening cognitive behaviorwhile removing immuno suppressive activities appears to mitigate these Alzheimer s like pathologiesThese 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 reductionPolyamines are immuno suppressive mediators and polyamine levels increase in AD brainsDFMO is a potentorally available irreversible inhibitor of the key enzyme required for polyamine synthesisOrnithine DeCarboxylaseODCThusour 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 ADDFMO 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 marketedmaking commercialization a challengeWe have solved this problem by creating novel prodrugs of DFMO that reduce polyamine levelsare orally availablemay not have the same undesirable side effect profile as DFMO aloneand are patent pendingTavares and VitekWOAIn Phasewe successfully created DFMO prodrugs and characterized them in vitroIn Phasewe are proposing to continue development of DFMO prodrugs by making additional prodrugscharacterizing them in vitro and in vivodetermining whole animal pharmacokinetic and pharmacodynamic profilesand testing them in the CVN AD mouse modelThese additional activites are laying the groundwork for selection of a lead and a backup compoundan important milestone on the critical path that will be taken into clinical development of Resilio s DFMO prodrugs for an Alzheimer s indication