Project 3 of the program application will test polyamine biosynthesis inhibitors (PBIs) for the treatment ofHlV-associated dementia (HAD) based on the hypothesis that macrophage activation is central to thepathogenesis of this disease process. This project will be housed within the Hawaii AIDS Clinical ResearchProgram (HACRP, PI: Cecilia Shikuma) University of Hawaii John A. Burns School of Medicine, and will beperformed in close collaboration with the central core laboratory at Pathologica (Project 1, Cores B and C)and with the simian PBI trials conducted at Harvard (Project 2). Project 3 will utilize banked specimens fromour NINDS-funded Hawaii Aging with HIV Cohort (HAHC) and generate data in vitro testing whether HIV-infectedactivated M/MOs from HAD patients are preferentially killed by PBIs. In tandem, we will identifypatients with HIV cognitive impairment in real-time using an abridged combination of neuropsychologicaltests (NPZ-4) shown to correlate highly with the diagnosis of HAD in our patients. In these patients, we willdefine the unique blood M/MO gene and protein expression pattern ('ProMac Profile') associated withneurocognitive dysfunction. Finally, working closely with our collaborators, NIMH and the FDA, we proposeto recruit subjects with HAD from HAHC participants who performed poorly on NPZ-4 testing, and launch, inthe later half of the second year of funding, a phase 1 clinical trial of a PBI drug targeting HAD.The strengths of this proposal lie in our existing HIV clinical trials infrastructure, our neurocognitively well-characterizedpatient and banked specimen resources of the Hawaii Aging with HIV Cohort, and thetranslational research expertise of our team with a track record of close collaboration among the Programinvestigators.
The specific aims as proposed will extend our knowledge of the pathogenesis of HAD andassess the safety and potential efficacy of a class of chemical compounds specifically directed against thelikely central mechanism involved in the development of HAD.
Specific Aim 1) Utilizing banked specimens, to determine in vitro the killing potential of the selected PBI(s)against activated M/MOs from subjects with HAD; and to assess various factors (HIV DNA, novel activationflow markers) potentially related to its efficacy. Hypothesis to be tested: 1) PBIs will demonstrate effectivekilling of activated M/MOs from HAD subjects, 2) High HIV DNA within activated M/MOs will correlate toenhanced killing by PBIs, 3)High levels of novel activation flow markers will correlate to enhanced killing byPBIs.
Specific Aim 2) To define the 'ProMac profile' (blood M/MO gene and protein expression patterns)associated with neurocognitive impairment using fresh specimens captured in real-time within the HawaiiAging with HIV Cohort, and to evaluate the killing potential of PBIs against M/MOs with this profile.Hypotheses to be tested 1) A unique 'ProMac profile' will be found in M/MOs isolated from HIV-infectedsubjects with neurocognitive dysfunction, 2) M/MOs with this 'ProMac profile' will be preferentially killed byPBIs.
Specific Aim 3) To conduct Phase 1 clinical trials utilizing a PBI drug in individuals with HAD.Hypothesis to be tested 1) PBIs given to patients with HAD will be safely tolerated and will result in adecrease in biomarker(s) indicative of a persistently activated M/MO phenotype.
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