CALIFIA BIO

March 15, 2011-- Califia Bio Phase 1 SBIR Grant for “Selectively Non-Selective” Kinase Inhibitors for Treatment of HIV Induced Synaptodendritic Damage. Califia Bio has been awarded a NIMH Phase 1 Small Business Innovative Research Grant for the discovery of potential treatments for HIV-Associated Neurocognitive Disorder (HAND).

Combination anti-retroviral therapy slows the progression of HAND but does not stop HIV mediated destruction of the synaptic wiring of the brain. The disease results from (1) a dysregulation of inflammatory cytokines and chemokines, (2) the recruitment of immune cells (inflammatory leukocytes) to the CNS, (3) viral infection of glia leading to interruption of their normal function of preserving synapse connections, and (4) extensive synaptodendritic damage. Numerous inflammatory mediators are implicated in this cascade in cellular models, where TNFα release and signaling likely play a major central role. A more limited subset of mediators has been identified as being up-regulated in the CSF and post-mortem brain tissues of HAND patients. These translationally validated mediators/effectors include TNFα, the monocyte chemoattractant MCP-1, and mixed lineage kinase type 3 (MLK3), an important control point in MAPK kinase regulated inflammation pathways. We are identifying and validating major “control hubs” (i.e. critical kinases) in the pathways leading to HAND by developing small molecule inhibitors directed at a panel of validated mediators/effectors. Recent strategies in kinase drug discovery now recognize that the most efficacious drugs modulate multiple kinase pathways, but the issue remains finding safe compounds with multiple activities. Our efforts will elucidate new pathways/networks/control nodes involved in the neuropathogenesis of HAND, and will identify novel compounds to inhibit them.