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Therapeutic Core

Barbara SlusherDr. Barbara Slusher, Core Director

Core Mission:

The mission for the Therapeutics Core is to facilitate new adjunctive therapeutics development for the treatment of HIV-associated cognitive disorders. The Therapeutics Core will utilize techniques in neurobiology, medicinal chemistry, biopharmaceutics profiling, and pharmacokinetic analysis as a combinatorial approach to identify and develop these therapies. HIV-associated neurocognitive disorders (HAND) remain very prevalent, even among HIV-infected individuals who have been treated with highly active antiretroviral therapy. Thus, there is an unmet medical need to develop adjunctive therapies to treat HAND. Our previous studies in the Therapeutics Development core of the JHU NIMH Center for Novel Therapeutics have demonstrated that neuroprotective and/or neuroregenerative small molecule regimens protect vulnerable hippocampal and cortical neurons from oxidative stress and HIV viral proteins in vitro and in vivo, and therefore, may provide such a treatment for HAND.

Goals and Objectives:

  • To use focused medium throughput screening, using in vitro models to identify novel compounds useful for treatment of HIV-associated cognitive dysfunction with the over-arching theme of reducing the sustained CNS inflammation that we believe underlies the development of HAND
  • To evaluate potential neuroprotective and neuroregenerative compounds in vivo
  • To facilitate preclinical development of potential neuroprotective/neuroregenerative therapeutic agents, identified internally and by external investigators.

Education:

The Therapeutic Core takes full advantage of the Johns Hopkins Drug Discovery (JHDD) program, and is committed to reaching younger researchers through several drug discovery seminars, symposium, and graduate courses. The Johns Hopkins Drug Discovery web site details these activities, and is also used proactively to increase the awareness of the Center as the Therapeutic Core.

Johns Hopkins Drug Discovery Program will offer “Drug Discovery Case Studies” (ME:200.707)” in the 2016 Fall Semester. In this course, each lecture selects a particular drug and examines some key elements that have contributed to its successful discovery and development. The final three lectures will be given by guest speakers who will present case studies on new drugs in which they were directly involved at the time of discovery and development. Please see attached syllabus for additional details about the course.

A truncated version is also available at: https://drugdiscovery.jhu.edu/our-courses/drug-discovery-case-studies/

If you have any questions about the course, please contact Takashi Tsukamoto (ttsukamoto@jhmi.edu).

Recent Publications 

  • Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC. HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol. 2016 Apr;12(4):234-48. doi: 10.1038/nrneurol.2016.27. Epub 2016 Mar 11. Review. PubMed PMID: 26965674; PubMed Central PMCID: PMC4937456.
  • Figuera-Losada M, Stathis M, Dorskind J, Bandaru VV, Westwood NJ, Rogers GW, McArthur JC, Haughey NJ, Slusher BS, Rojas, C. "Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties.”  PLoS One. 2015 May 26;10(5):e0124481. doi: 10.1371/journal.pone.0124481. eCollection 2015.
  • Xiang Y, Stine ZE, Xia J, Lu Y, Altman BJ, Hsieh AL, Thoma AG, Gao P, Zhang H, Yan B, Slusher BS,  Zhuo J,  Ooi LL,. Lee CGL, Mancuso A, Le A, Rayport S, Felsher DW, Dang CV.  “On-target inhibition of glutaminase diminishes cell autonomous tumorigenesis.” J Clin Invest. 2015 Jun;125(6):2293-306. doi: 10.1172/JCI75836. Epub 2015 Apr 27.
  • Alt J, Potter MC, Rojas C and Slusher BS. “Bioanalysis of the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) in plasma and brain by mass spectrometry.” Anal Biochem., 2015 Apr 1;474:28-34.
  • Figuera-Losada M, Rojas C, Slusher BS.  “Inhibition of microglia activation as a phenotypic assay in early drug discovery.” J of Biomolecular Screening, 2014 Jan;19(1):17-31
  • Thomas A, O'Driscoll, CM, Bressler J, Kaufmann W, Rojas CJ, Slusher BS. “Small molecule glutaminase inhibitors block glutamate release form stimulated microglia.” Biochem Biophys Res Commun. 2014 Jan 3;443(1):32-6
  • Coughlin, JM, Wang Y, Ma S, Yue C, Kim PK, Adams AV, Roosa HV , Gage KL, Stathis M, Rais R, Rojas C, McGlothan JL, Watkins CC, Sacktor N, Guilarte TR, Zhou Y, Sawa A, Slusher BS, Caffo B, Kassiou M, Endres, CJ, Pomper MG. “Regional Brain Distribution of Translocator Protein using [11C]DPA-713 PET in Individuals Infected with HIV.” J Neurovirol. 20.3 (2014): 219-232.
  • Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CG, Tatonetti N, Slusher BS, Stockwell BR. “Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis.” eLife 2014 May 20;3:e02523
  • Slusher BS. “Drug Discovery Goes Back To School: Changing Ecosystem of Drug Discovery and the Rising Role of Academia.” J Peripheral Nervous System, 19.S2 (2014): S2-S4.

Highlighted Publications

Publication: Inhibition of microglia activation as a phenotypic assay in early drug discovery.

microglia chartFigure 2 Schematic representation of work flow for primary and secondary phenotypic assay screening strategies based on microglial activation. SAR, structure-activity relationship.

ABSTRACT: Complex biological processes such as inflammation, cell death, migration, proliferation, and the release of biologically active molecules can be used as outcomes in phenotypic assays during early stages of drug discovery. Although target-based approaches have been widely used over the past decades, a disproportionate number of first-in-class drugs have been identified using phenotypic screening. This review details phenotypic assays based on inhibition of microglial activation and their utility in primary and secondary screening, target validation, and pathway elucidation. The role ofmicroglia, both in normal as well as in pathological conditions such as chronic neurodegenerative diseases, is reviewed. Methodologies to assessmicroglia activation in vitro are discussed in detail, and classes of therapeutic drugs known to decrease the proinflammatory and cytotoxic responses of activated microglia are appraised, including inhibitors of glutaminase, cystine/glutamate antiporter, nuclear factor κB, and mitogen-activated protein kinases.

Publication: Regional Brain Distribution of Translocator Protein using [11C]DPA-713 PET in Individuals Infected with HIV.

Regional brainFig. 6 Plots using GMVT showing the trends among healthy controls, HIV asymptomatic, mild impairment, and HIV dementia sub-cohorts (mean and standard deviation shown for each region)

ABSTRACT: Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [(11)C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [(11)C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test-retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.

Core Members

Barbara Slusher, Ph.D., M.A.S. (Core Director)
Camilo Rojas, Ph.D. (Co-Investigator)
Takashi Tsukamoto, Ph.D. (Co-Investigator)
Rana Rais, Ph.D. (Co-Investigator)
 

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