Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 1

NeuroAIDS: Bidirectional Translation of Molecular Targets in the Development of Novel Therapeutic Strategies

Harris A. Gelbard, M.D., Ph.D.
University of Rochester Medical Center

NeuroAIDS continues to be a neurologic healthcare problem of paramount importance, with approximately half of the one million people currently infected with human immunodeficiency virus type 1 (HIV-1) in the U.S. having neurologic disease due to CNS infection. Highly active antiretroviral therapy (HAART) has slowed the onset, and in some cases temporarily reversed the symptoms of HIV-associated neurologic disease, but has not altered the prevalence of neurologic disease. Thus we hypothesize there is a reversible metabolic component of HIV-1 associated neurologic disease with molecular targets that we can define in laboratory models, design rational adjunctive neuroprotective drugs for, then test in in vitro and in vivo models of NeuroAIDS, and ultimately bring the most successful drugs to Phase 1 trials. Based on pre-clinical data, we have previously identified glycogen synthase kinase 3 beta (GSK-3β) as an enzyme complex in vulnerable neurons that is disrupted by HIV-1 neurotoxins, and then successfully used the GSK-3β inhibitors, sodium valproate (VPA) and lithium in Phase 1 trials. Preliminary spectroscopic data from brain imaging studies and neuropsychologic evaluation of our patient cohort with HIV-1 and neurologic disease supports advancement of VPA for consideration in Phase II trials of efficacy. Additionally, we have built on our experience with successfully investigating the kinome to identify a molecular target of equal or greater importance than GSK-3β in the pathogenesis of HIV-1 associated neurologic disease, mixed lineage kinase 3 (MLK3) that is activated by HIV-1 neurotoxins to induce inflammation and neuronal damage. Our preliminary pre-clinical data supports our hypothesis that MLK3 inhibition results in microglial deactivation as well as preservation of synaptic structure and function in in vitro and in vivo models of NeuroAIDS. Based on these findings, we will perform pharmacokinetic Phase 1a and1b trials with a first-generation MLK3 inhibitor that has been advanced to clinical trials for Parkinson’s disease. Additional secondary outcome measures of MRS imaging studies and proteomics profiling of leukocytes to predict disease progression and potential response to treatment will be performed. Partnering with Biofocus Discovery, a Galapagos company, we have initiated further molecular studies of MLK3 to design a new drug, with improved neuroprotective efficacy and CNS-penetrant characteristics, in order to ultimately develop a second-generation MLK3 inhibitor. Our research program as configured defines a paradigm for a bench-to-bedside neuroprotective strategy based on MLK3 inhibition.

Support: MH64570;MH56838;MH078989;NS31492

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