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Novel, Orally-Available Prodrugs for Alzheimer's Disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44AG051285-02A1
Agency Tracking Number: R44AG051285
Amount: $1,858,620.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIA
Solicitation Number: PA16-302
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-09-01
Award End Date (Contract End Date): 2020-05-31
Small Business Information
Durham, NC 27709-0002
United States
DUNS: 080291049
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 308-1341
Business Contact
Phone: (919) 656-7835
Research Institution

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

* Information listed above is at the time of submission. *

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