Autophagy-based HDT for tuberculosis



 DESCRIPTION (provided by applicant): The objective of this project is to convert the therapeutic potential of autophagy to an autophagy-based host- directed therapy (AB-HDT) for control of tuberculosis (TB). The specific emphasis will be on treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains. The reasons for this target is that treatment options for MDR-TB are severely limited and drug regimens are less active, lengthy, toxic, expensive and often ineffective so the need is greatest in drug resistant TB; a second reason is the greater ease of assessing efficacy of AB-HDT in this patient population. Data in experimental animal models indicate dual effects of autophagy each attractive for an AB-HDT in TB: direct promotion of bacterial killing and inhibition of injurious inflammation. We have formed a team between basic (Deretic, Timmins, Salgame) and clinician scientists (Ellner, Horsburgh, Joloba) to guide, coordinate, and execute the UH2 and UH3 phases to deliver practical results and test the hypothesis that AB-HDT can be used against Mtb and prove beneficial and practical in the clinical setting. We propose to select the candidate drug and dosage schedule based on determination of comparative efficacy in preclinical models including U2 clinical studies with healthy human subjects, pharmacokinetics/pharmacodynamics (PK/PD) studies, consideration of adverse events profile. In the UH2 phase, we will use cellular and murine models of autophagy to compare, test and optimize enhancement of autophagy by a panel of candidate AB-HDT drugs. We will then test the top AB-HDT drugs for efficacy in the mouse model of TB. The agonist drugs to be compared during the UH2 phase will be those with evidence of efficacy in mouse TB models and those identified in our GGC autophagy-inducing compound screen: carbamazepine, gefitinib, imatinib, bosutinib (a back up for imatinib), bromhexine (from GGC screen), sertraline, atorvastin, metformin and an "open position" AB-HDT drug. The key deliverable of the UH2 phase will be identification of candidate HDT drugs showing potential for clinically meaningful efficacy in standard mouse aerosol models of TB. The results of the mouse model will be integrated with known pharmacologic and safety properties of the drugs to identify the most beneficial AB-HDT regimen will be moved to the UH3 phase. In the UH3 phase, we propose to study patients with MDR-TB (±HIV co-infection) in Uganda because the burden of dual infection is greatest in Sub-Saharan Africa and to assure that AB-HDT exerts a therapeutic effect in HIV-infected TB patients. We will recruit MDR-TB cases in Kampala Uganda, selected as a clinical site because of long-standing collaboration including studies of MDR-TB, the state-of-the art, CAP-certified, mycobacterial reference and research laboratory appropriate to assure high quality bacteriologic endpoints, and access to sufficient numbers of HIV-infected and HIV-uninfected MDR-TB cases. These studies will establish whether an AB-HDT is sufficiently promising to warrant a Phase IIB/III clinical trial with clinical efficacy as an endpoint.