Development and Validation of a Chronic Lung Non-Tuberculous Mycoplasma (NTM) Infection Model Using a Micro-Physiological System (MPS) and Mycobacterium abscessus as a Model NTM microorganism

The goal is development of a chronic lung infection model for Non-Tuberculosis Mycobacterium in a Microphysiological System format. The model will be an "Airway-On-A-Chip", leveraging technical advancements in microfluidics and mimicking of human organ functions; in this case, the human lung airway. Initially, normal human lung airway cells will be used. The Airway-On-A-Chip will be characterized using measurable parameters to demonstrate the cells are functioning as expected. Ideally, the start-up time for this portion of the modeling work will be minimal, if the contractor selected already has the exact or similar model available. This initial format will be infected with a Non-Tuberculosis Mycobacterium with the aim of maintaining the infection up to 30 days. A standard of care drug against the Non-Tuberculosis Mycobacterium will be introduced to the chronic infection model to demonstrate that drug efficacy can be shown. Then, a candidate drug against the Non-Tuberculosis Mycobacterium will be evaluated for efficacy in this model. A second model will be set up with lung airway cells derived from a subject with Cystic Fibrosis. This Airway Chip will likewise be characterized using the similar measures as used with the "normal" format as well as additional parameters characteristic of the cystic fibrosis lung epithelium. This model will be infected with a Non-Tuberculosis Mycobacterium and also followed for up to 30 days. The same standard of care drug used previously will be evaluated for efficacy in the cystic fibrosis model. Subsequently, the cystic fibrosis model will be used for evaluation of candidate drugs against the Non-Tuberculosis Mycobacterium.

The annual infection rate for Non-Tuberculosis Mycobacterium infections in the U.S. grew by roughly 3.5% to 8% per year over the last decade. In a recent article (BMC Infect Dis. 2024 Oct 2;24(1):1094. doi: 10.1186/s12879-024-09965-y. PMID: 39358723; PMCID: PMC11445848), it was concluded that, "...a need [exists] for improved healthcare planning...as well as improved diagnostics and therapeutics to better detect and treat NTM PD in populations aged 65 years...". Therefore, the availability of better models to enable evaluation of new therapeutics against Non-Tuberculosis Mycobacterial infections, and especially chronic infections, is an urgent matter. Since the priorities set forth by the administration include both, the development of more non-animal models (NAMs) and addressing chronic infections, this work would help to fill a very important gap in our ability to respond to this growing problem of Non-Tuberculosis Mycobacterial infections. If this model is not developed, this could negatively impact the development of efficacious medications to fight this infection.