1. Preclinical Pathway to Host-Directed Therapy for TB/HIV Co-Infection
WGND Workshop
GRC Tuberculosis Drug Discovery and Development
6/27/2017
Daniel Frank
Tuberculosis Clinical Research Branch
DAIDS/NIAID

2. Importance of Host Directed Therapy
Antibacterial drug development for TB is inadequate because of lack of incentive and drug resistance continues to increase
Traditional vaccine approaches have failed for TB and HIV
New discoveries and precision medicine interventions have revolutionized therapy by safely reversing effects of molecular drivers of disease that affect fundamental/core cell regulatory pathways
Pathogens disrupt functions of immune cells essential for host defense by modulating many of these same core cellular pathways

3. RFA-AI-14-058 Host-Directed TB Therapy: New Approaches
First generation gents selected as anti-inflammatory and generally well tolerated, or empirically
Imatinib
Statins
IL-1 antagonist
Autophagy inducers
2 year UH2 award for preclinical development and clinical trial planning
3 year UH3 award for proof of concept clinical trial

4. Next-Generation Candidate HDT Agents
Guided choices from the many target agents designed to reverse abnormalities in cell regulatory caused by microbial pathogenesis:
MAPK TKIs Mevalonate metabolism
Rho/Rock SIKs Keap1
RAS –MEK-ERK TNF/Ikk-β DPP-4
PI3K-AKT-mTOR PTEN/p53 Sphingosine1 kinase
PARPs Notch cAMP-PKA
Sirtuins Hedgehog HIF-1α
CD38/AMPA channel GSK-3β Angiotensin II receptor
AMPK cyclins/CDKs Cyclophilin D

5. Dysregulation of Immune Cell Regulatory Pathways by Mtb in the Context of HIV Infection
RFA-AI (R61/R33)
Due date: August 1, 2017
R61 Phase research will include hypothesis-based, milestone-driven preclinical studies focused on identifying changes in infected macrophages/dendritic cells, and subsequent changes in uninfected immune cells, as well as how HIV co-infection alters Mtb-induced cellular changes. Specific molecular immune cell regulatory changes induced in Mtb or Mtb/HIV infected cells will be delineated as potential targets for therapeutic intervention.  Identification and characterization of target molecules will inform efforts to test interventions for the affected immune response control pathways.
R33 Phase research will support preclinical proof of principle studies by modulating the target to confirm its immunopathogenic relevance, and to begin therapeutic agent identification/evaluation in an appropriate model system. Strategies may include the use of targeted small molecules, biologics, miRNA, or other methods of restoring host immune regulation, and evaluation of changes in bacterial load, immune cell bactericidal activity, inflammatory control, and prevention of tissue damage.