cART has dramatically changed the phenotype of HIV-associated neurocognitive disease (HAND), but has neither eradicated it or decreased its prevalence. Thus we hypothesize there is a reversible metabolic component of HIV-1 associated neurologic disease with the molecular target of mixed lineage kinase type 3 (MLK3) that we can define in laboratory models, design rational adjunctive neuroprotective drugs for using our series of lead compounds URMC-099c*, then test in our in vitro and in vivo models of NeuroAIDS, with the goal of advancing the most efficacious development compound to the FDA for IND filing within this grant cycle. In the previous cycle, we validated MLK3 as an enzyme pathologically activated by HlV-1 neurotoxins, then successfully developed a small molecule MLK3 inhibitor, URMC-099 capable of achieving therapeutic concentrations in the CNS. For this competing renewal application, we have built on our experience with our industry partner to synthesize a series of small molecule MLK3 inhibitors with drug-like properties for testing in our models of HAND that investigate neuroinflammation and synaptodendritic damage. Thus, our administrative Core A will coordinate all projects and cores as follows: Project 1 will test novel URMC-099c* developed by our industry partner, Califia Bio, Inc (Project 2) to determine in vitro and in vivo endpoints of MLK3 inhibition in preventing neuroinflammation and synaptodendritic damage. Project 1 will use mathematical modeling and biostatistical expertise in Sub-Core A, supported by the URMC D-CFAR to formulate algorithms of efficacy for advancement of URMC-099c* in Projects 2 and 3. Project 2 will use a hypothesis-driven testing funnel with models developed in Project 1 to advance the synthesis of URMC-099c* to development compound (i.e. final drug formulation). Project 3 will test the most efficacious of URMC-099c* in a CD34 chronic murine model of HAND using novel in vivo neuroimaging (magnetic resonance spectroscopy, diffusion tensor imaging, SPECT) techniques to assess neuroprotection. Additionally, in the latter half of this program, Project 3 will test the efficacy of our development compound in a chronic monkey model of HAND with support by the UNMC P30 """"""""CHAIN"""""""" Center. With the support of the URMC CTSI, Core A will then apply to the NIH Rapid Access for Interventional Development (RAID) program for good laboratory practice (GLP) scale-up and manufacture, as well as remaining safety and toxicity studies of our development compound, prior to filing an IND with the FDA. Our PPG as configured defines a paradigm for a bench-to-bedside path to adjunctive therapy based on MLK3 inhibition.

Public Health Relevance

This program project will use expertise in medicinal chemistry, immunology, virology and neuroscience to develop a new drug for testing in preclinical models of HlV-1 associated neurocognitive disease (HAND). At the end of this project period, the group will apply to the NIH RAID program for support in scaling up the synthesis, manufacture and safety testing of this drug for investigational new drug (IND) filing with the FDA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH064570-13
Application #
8664421
Study Section
Special Emphasis Panel (ZMH1-ERB-M (04))
Program Officer
Colosi, Deborah
Project Start
2001-09-30
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$1,344,864
Indirect Cost
$227,577
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22
Dong, Weiguo; Embury, Christine M; Lu, Yaman et al. (2016) The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation 13:184
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Olson, Katherine E; Bade, Aditya N; Schutt, Charles R et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease. Neurotherapeutics 13:635-46
Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi et al. (2016) Neuropharmacologic Approaches to Restore the Brain's Microenvironment. J Neuroimmune Pharmacol 11:484-94
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James et al. (2016) Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond) 11:1913-27
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Bade, Aditya N; Gorantla, Santhi; Dash, Prasanta K et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Mol Neurobiol 53:3286-97

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