Targeting host lipid homeostasis to augment anti-mycobacterial treatment

Challenge

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The emergence of multi-drug resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR) Mycobacterium tuberculosis (Mtb) strains severely jeopardizes control of TB epidemic (according to WHO [2016]: 10.4 million new cases, 1.5 million deaths), urgently necessitating alternative approaches to improve TB treatment and control. A novel strategy to fight TB without incurring the risk of bacterial resistance development is to target host structures or molecules that facilitate Mtb replication.

Technology

Mtb has evolved to reside within the hostile environment of lipid-laden human macrophages, and to access these lipids as predominant carbon source. Investigating foamy macrophages within the lungs of TB patients and experimentally infected mice, the inventors found that Mtb promotes an accumulation of neutral lipids in the host via WNT6-induced expression of key lipid metabolic enzymes including acetyl-CoA carboxylase-2 (Acc2). Accordingly, the host`s lipogenesis provides a novel target for a host-directed TB therapy. Inhibition of lipogenesis in general and Acc2 in particular has been extensively studied in the past by various Pharma/Biotech companies in the context of metabolic disorders, like obesity and NASH. Various Acc inhibitors have been developed for this indication, and could now be repurposed for anti-TB therapy. The therapeutic concept foresees co-treatment with Acc2 inhibitor and standard and novel anti-TB drugs to significantly improve conventional TB therapy.

Commercial Opportunity

The proprietary technology is available for in-licensing and co-development.

With regard to the latter, the Research Center Borstel – Leibniz Lung Center has (i) extensive scientific expertise in the field of TB research (e.g. member of the German Center for Infectious Disease [DZIF], harboring major parts of the Thematic Translational Unit TuBerculosis [TTU TB], member of the German Center for Lung Research (DZL-ARCN), host of the national and WHO supranational Mbt reference centers), (ii) established two mouse models with human TB pathology, and (iii) a clinic and Center for Clinical Studies (focus on lung diseases), prepared to conduct (if applicable) first studies in TB patients, and possibly to participate in further clinical trials.

Development Status

The inventors have tested several Acc inhibitors in different in vitro models using murine and human macrophages, and observed a significant concentration-dependent inhibition of Mtb growth. Notably, the Acc inhibitors showed no direct affect against Mtb, and were not toxic to macrophages. Moreover, additive growth inhibitory effects were observed in human macrophages when Acc2 inhibition was combined with suboptimal concentrations of the first line anti-TB drug isoniazid. The therapeutic concept has further been challenged in vivo to prove that Acc inhibitors are also able (i) to inhibit Mtb growth in animal models, and (ii) to significantly improve standard TB therapy (i.e. using isoniazid, INH).

Patent Situation

A priority-establishing EP application has been filed on July 7th, 2016, followed by an international PCT application in July 2017. Most recently, the PCT application has been extended to Europe, the US, Japan and Russia.

Further Reading

Julius Brandenburg et al. (2019) Mycobacterium tuberculosis exploits WNT6-induced Acetyl-CoA Carboxylase-2 driven perturbation of host lipid homeostasis to facilitate growth in macrophages. Nature Immunology, under revision.

Reiling & Brandenburg (2018) ACC inhibitors for use in treating mycobacterial diseases. WO/2018/007430.