Novel Therapy Approach for Treatment of Lung Fibrosis

Challenge

Due to a high level of complexity and patho-mechanisms that are not yet understood, there are currently hardly valid approaches to specifically investigate the molecular processes that lead to the development of fibrosis or to enable the development of drugs against fibrotic changes in various organs. The associated forms of the disease are therefore only treatable to a limited extent and represent a significant health problem responsible for over 30% of all global death.

Technology

This novel therapy approach is based on the findings that fascia and the transfer of pre-existing extracellular matrix (ECM) plays a crucial role in tissue scarring and organ fibrosis. Physical translocation of pre-existing matrix elements to areas of injury were identified as a novel molecular mechanism for fibrosis initiation. In particular, it was demonstrated that mesothelial cells are causative for such ECM movement. By targeting said mesothelial cells, which form the surface cell layer as the outermost lining of each internal organ, and inhibiting movement of pre-existing ECM towards a site of organ injury, fibrosis initiation and progression could be prevented. For this purpose, cystatin A, a natural inhibitor of the thiol proteases cathepsin B, H and L, was selected as the preferred treatment approach to directly address the pleural surface of the lung. It inhibits mesothelial cathepsin B which releases pleural matrix and aggravates pulmonary fibrosis component being identified as crucial step for mobilization of pre-existing ECM into lung tissue. Intrapleural injections enable direct manipulation of mesothelial cells facing the pleural cavity. Thus, AAV vectors of the AAV2/8 serotype were used as vehicles and applied intrapleurally with the corresponding therapeutic target genes. In mice, an efficient blockade of the release of fluid matrix components after tissue damage by bleomycin was achieved which prevented ECM movement and fibrotic tissue generation. Cathepsin-mediated cleavage of ECM components was identified as crucial step for mobilization of pre-existing ECM into lung tissue. Analysis was performed by labelling preexisting extracellular matrix (ECM) on the surface of different internal organs with N-Hydroxysuccinimide-esters in chemical and viral models of fibrosis in mice, as well as in ex-vivo human samples.

Commercial Opportunity

The anti-fibrotic therapy approach and ECM labeling assays are available for in-licensing.

Development Status

Proof of concept experiments were performed in mice.

Patent Situation

WO2023/079127A1 has been nationalized in US, CA, EP, CN, JP, SG, AU, IL. IP portfolio on ECM movement modulation and in vitro and in vivo assay systems (WO2020/157122A1; WO2021/028596).

Further Reading

Fischer, A., Han, W., Hu, S. et al. Targeting pleuro-alveolar junctions reverses lung fibrosis in mice. Nat Commun 16, 173 (2025). doi.org/10.1038/s41467-024-55596-x

• Correa-Gallegos et al., Nature 2019; doi:10.1038/s41586-019-1794-y

• Jiang et al., Nature Communications 2020; doi:10.1038/s41467-020-19425-1

• Wan et al., Matrix Biology 2021; doi: 10.1016/j.matbio.2021.01.005

• Fischer et al., Nature Immunology 2022; doi:10.1038/s41590-022-01166-6

• Fischer et al., Nature Protocols 2023; doi.org/10.1038/s41596-023-00867-y