Periodic Reporting for period 2 - iPSC2Therapy (From iPSC-Macrophage Biology Towards Regenerative Therapies Targeting Respiratory Infections)
Reporting period: 2021-07-01 to 2022-12-31
Infection of the lower respiratory tract (LRTI) are still associated with high morbidity and mortality, highlighting the utmost need for novel therapeutic options. In fact, several pathogens can cause LRTI and the current COVID-19 pandemic underlines the importance/thread of viral pathogens. Despite viral intruders, also bacterial and mycobacteria can cause a variety of life-threatening infections, which can be become hard to treat, if the respective pathogen is resistant to the current standard of care such as antibiotics. Of note, alveolar macrophages in the lung are the most abundant cell type in the bronchioalveolar space, able to sense and to clear various types of intruders. Recent knowledge in the biology of macrophages and in particular alveolar macrophages is pointing towards a strong therapeutic potential of these cells. In the past decade, alveolar macrophages have been associated with the onset and progression of a variety of lung diseases incl. pulmonary infections. Given the important role of macrophages in (myco)bacterial infections and recent innovations in the field of regenerative medicine, the iPSC2Therapy proposal will apply the technology of induced pluripotent stem cell (iPSC) technology to elaborate the anti-mycobacterial properties of iPSC-derived macrophages, all directed towards the development of novel cell-based immunotherapies targeting bacterial airway infections. This ambitious aim is combined with seminal insights into the developmental trajectories of human macrophages, with the overall goal to improve current macrophage-manufacturing pipelines and to generate macrophage-cell products which show a therapeutic effect upon intra-pulmonary transplantation. Overall, the work of iPSC2Therapy lays the foundation for new cell-based immunotherapies for the lung and other tissues with direct impact for patients suffering from mycobacterial lung infections and beyond.
Work performed within iPSC2Therapy already provided novel insights into driving forces of early hematopoietic development and the onset of human myeloid progenitors and macrophage. Manipulating the ontogeny of macrophages is of great importance, as it now allows for the development and further improvement of cell manufacturing techniques. In fact, insights into the important role of cytokines could lay the foundation for production pipelines for human macrophages, which can be performed in scalable bioreactor systems using fully defined media. Such improvement and the possibility to apply different kind of bioreactors is unique and paved the way for the use of iPSC-derived macrophages against bacterial airway infections. Both, Pseudomonas aeruginosa (PsA) and Staphylococcus aureus (SA) have high clinical relevance and work within the framework of iPSC2Therapy could prove the therapeutic activity of iPSC-Macrophages against these two pathogens. Current work goes beyond these two pathogens, investigating the therapeutic benefit against Mycobacterial pathogens.
As of yet, the standard of care for bacterial airway infections are antibiotics. To overcome the global threat of anti-microbial resistance (AMR), current efforts concentrate on the development of novel immunotherapies, which are able to manipulate the function of cells. The work of iPSC2Therapy goes beyond these concepts and aims to combine stem cell innovations with modern infection medicine, developing macrophage-based cell products which are able to counteract (myco)bacterial airway infections. Seminal insights into the developmental trajectories of human macrophages pave the development of defined subsets of human macrophages, which can be used in a variety of (non)therapeutic applications. At the end of iPSC2Therapy, we envision to have unique pipelines for the production of human macrophages established and to have a novel cell-based immunotherapy concepts for mycobacterial infections in place, which can further be advanced towards other lung diseases and beyond.