Combination antiretroviral therapy (cART) has slowed the onset, but has not altered the prevalence of HIV - associated neurologic disease. In aging patient populations, the prevalence of HIV-1 associated neurocognitive disorder (HAND) may be increasing, despite the ability of cART to reduce viral load in the CNS to undetectable levels, such that half of the population living with HIV may experience symptoms of HAND. The hallmarks of HAND include: 1) a dysregulation of inflammatory cytokines and chemokines, 2) the recruitment of immune cells (monocytes) to the central nervous system (CNS), 3) the viral infection of glia leading to interruption of their normal function, and 4) extensive synaptodendritic damage. A host of inflammatory mediators are implicated in this cascade, where TNF-1 release and signaling likely play a major central role. A more limited subset of mediators has been identified as being up-regulated in the cerebrospinal fluid and post- mortem brain tissues of HAND patients. These translationally validated mediators/effectors include TNF-1, the monocyte chemoattractant MCP-1, and mixed-lineage kinase 3 (MLK3), an important control point in MAPK kinase regulated inflammation pathways. In collaboration with Dr. Harris Gelbard and Stephen Dewhurst at the University of Rochester Medical Center, we have identified URMC-099, a compound that inhibits MLK3 and blocks up-regulation of MCP-1 and TNF-1 and other inflammatory mediators in HIV-1 Tat stimulated human macrophages. The University of Rochester team has developed an in vivo imaging assay to evaluate the effects of HIV neurotoxins and potential drugs that may ameliorate their effects. In vivo brain imaging experiments in mice exposed intracerebrally to HIV-1 Tat have shown that i.p. administration of URMC-099 prevents Tat-induced leukocyte infiltration and microglial activation, and dramatically reverses Tat-induced damage to synaptic architecture. The damage to synaptic architecture is the key pathological process of HAND in damaging cognition and memory. Califia Bio is identifying and validating major """"""""control hubs"""""""" (i.e. critical kinases) involved in the pathways leading to HAND by developing small molecule inhibitors directed against them. We hypothesize that a compound with selective activity against the MLK family of kinases, and as yet unidentified kinases, may be more likely to be successful in blocking important signaling networks involved in the pathophysiology of the disease than a compound that selectively inhibits only MLK3, due in part to the functional redundancy of MLK signaling pathways. We have conducted kinome wide screens of activity for URMC-099;we also have now discovered lead MLK inhibitors with very different molecular scaffolds that cannot utilize the same binding modes in the MLK family of kinases. The goal of this application is to optimize and characterize these new lead series for their ability to interfere with pro-inflammatory mediators central to HAND and to identify the patterns of kinase inhibition exhibited by the best compounds. In Phase 2 we will seek development compounds with efficacy in animal models of HAND.
This Phase I SBIR proposal is aimed at the discovery of potential small molecule therapeutics to treat HIV/AIDS-associated mental and neurological disorders. In 2007, 33.2 million people worldwide were infected with HIV/AIDS. In the United States, it is estimated that more than 1 million individuals live with HIV, and an estimated 40,000 new HIV infections occur each year. It is estimated that as the population of HIV infected individuals ages, under the supportive care of combined antiretroviral therapy, as many as 50 percent of these patients will experience symptoms of HIV-associated neurological disease, which may range from severe dementia, to neuropathies and motor dysfunction.
