New method enables drug target validation for COPD treatment

Together with clinical partners, a team led by Dr. Dr. Melanie Königshoff and the doctoral student Franziska Uhl at the Comprehensive Pneumology Center of Helmholtz Zentrum München have investigated, for the first time, the suitability of Wnt/beta-catenin

activation to initiate repair in patient-derived COPD lung tissue. To achieve this, the researchers used a variety of chemical, biological and imaging techniques.

"In our study we showed that activation of the Wnt / beta-catenin ** - signaling pathway induces lung tissue repair, depending on the patient's stage of COPD," said Königshoff. The method developed by her team represents a powerful new tool for pathological assessment, drug validation, and mechanistic studies in patient-derived lung tissue, which will open novel avenues for successful clinical translation and precision medicine.

"Previously, studies largely relied on animal models, and cell cultures in the petri dish were limited to two dimensions and individual time points," said Uhl. The new method makes it possible to visualize diseased lung tissue of patients and possible repair mechanisms in 3D with high spatio-temporal resolution, providing valuable insight into lung pathologies and suitable therapeutic avenues.

This method closes the gap that formerly existed between target identification and preclinical validation of drug compounds and their application in the patient. "We hope in this way to develop long-term treatments that induce lung tissue repair in the patients," said Königshoff.

Next, the research team plans to expand the study by increasing the patient cohort, and further optimize new treatment approaches for patients with COPD. Moreover, the team is currently extending the application to other lung diseases such as pulmonary fibrosis and lung cancer.

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*COPD stands for chronic obstructive pulmonary disease, a chronic inflammatory pulmonary disorder that leads to a narrowing of the smaller airways. It occurs primarily in smokers and is often accompanied by excessive mucus production and shortness of breath during exercise.

COPD is a chronic inflammatory lung disease. An estimated 13 percent of adults over 40 years in Germany suffer from it. The disease causes high economic losses. It is characterized by excessive mucus production and shortness of breath during exercise as well as a loss of functional lung tissue, the alveoli. At present, COPD cannot be cured; it is only possible to slow the disease progression. Lung transplantation is the only curative option, but this remains the exception due to the small number of donor organs.

**The Wnt signaling pathway is one of the many pathways for the transduction of signals through which the cells can react to external changes. The signaling pathway is named after its key player "Wnt", a signaling protein that plays a major role as local mediator in the development of various animal cells. Numerous proteins are involved in the transduction of signals, including the beta-catenin protein.

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. DOI: 10.1183/09031936.00183214