TLC4PF

The Three Lakes Consortium for Pulmonary Fibrosis or TLC4PF was designed to identify potential treatments for PF using artificial intelligence and cutting-edge single cell profiling technologies and to validate efficacy of the molecules with human tissue-based models.  TLC4PF was comprised of 2 strategic workgroups: The Pulmonary Fibrosis Connectome led by Naftali Kaminski, MD, Professor of Medicine and Pharmacology and Chief of Pulmonology, Critical Care and Sleep Medicine at Yale University School of Medicine and PF Translation led by Melanie Königshoff, MD, PhD., Professor of Medicine and Associate Chief of Research at the University of Pittsburgh School of Medicine.

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news.yale.edu

Beyond the mouse model: Yale project advances treatments for lung disease

Building on their project, an atlas of human lung cells, researchers are exploring compounds, with the help of AI, that might reverse the scarring left by IPF.

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www.rarediseaseadvisor.com

New Venture Aims to Improve Diagnosis, Treatment of Pulmonary Fibrosis

Three Lakes Foundation, Yale University, and the University of Pittsburgh are joining forces to speed up the search for treatments for pulmonary fibrosis.

Consortium collaborators included laboratories run by Ivan Rosas, MD, Baylor School of Medicine, Jun Ding, PhD, McGill University Health Centre, Geremy Clair, PhD, Pacific Northwest National Laboratory (PNNL), Brigitte Gomperts, MD, UCLA Broad Stem Cell Research Center, and Kambez Benam, DPhil, University of Pittsburg.  

Key findings from the consortium include:

• Discovery that that cells phenotypically identical to IPF aberrant basaloid cells are present in diseases with acute lung injury like ARDs or COVID-19.
  

• Identification of the cellular sources of IPF aberrant basaloid cells and optimization of an ex vivo model for generating large numbers of these cells in a short period of time using normal human tissue.
  

• Creation of the Unagi webserver (McGill team) that allows users to explore cellular dynamics for each cell type and simulate perturbations.  The cellular dynamics in IPF progression can be reconstructed. This has enhanced the understanding of the changes that occur during disease progression.  Using the tool, a list of potentially therapeutic pathways/drugs were identified and many were experimentally validated.  This toolkit has the potential to significantly accelerate the drug development process.  “Unagi: Deep Generative Model for Deciphering Cellular Dynamics and In-Silico Drug Discovery in Complex Diseases” was published in Nat Biomed Eng. Reference
  

• Identification of important hallmarks not previously reported of the distal bronchial epithelium using proteomics, including a potential mesenchymal to epithelial transition resulting in higher deposition of fibrous collagen and the keratinization of this epithelium, potentially contributing to the physiopathology of IPF.

  
  

• An organoid model of IPF using IPF lung fibroblasts and induced pluripotent stem cell (iPSC)-derived Alveolar Type II cells (iAT2s) with the I73T Surfactant Protein C mutation was developed. This model was tested with approved drugs, drugs currently in clinical trials and drugs that failed in the clinic.  
  

• Improved 3D organoid model which allows analysis of patient derived cells.
  

• An SOP for processing and shipping of cold-preserved live and cryopreserved PCLS from both control donor and IPF explants between labs was optimized.
  

• The RNA extraction protocol was modified, leading to excellent quality and integrity RNA independent of the material used for filling.
  

• PCLS and single nuclear RNA sequencing were used to determine the effect of several compounds against specific targets in key fibrotic pathways. to validate their anti-fibrotic potential. One of the drugs tested, verteporfin, was shown to change the phenotype of basaloid cells in PF-PCLS. “Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis”, published in Nature Communications. Reference
  

• A 2-day workshop was held to discuss and summarize recent advances in the PCLS field.  The proceedings were summarized in “Precision-Cut Lung Slices: Emerging Tools for Preclinical and Translational Lung Research An Official American Thoracic Society Workshop Report” published in Amer. J. of Resp. Cell and Mol. Bio. Reference

These studies have advanced our understanding of the pathomechanisms involved in IPF and enabled the identification of potential novel drugs.  This project highlights the importance of collaboration between groups, especially computational biologists and experimental biologists and epitomizes the mission of TL12-20 to foster collaboration to accelerate development of therapies.

Additional Publications include:

• “Increased expression of CXCL6 in secretory cells drives fibroblast collagen synthesis and is associated with increased mortality in idiopathic pulmonary fibrosis”, published in European Respiratory Journal. Reference
  

• “Lung Cell Atlases in Health and Disease” published in Annual Rev. of Physiology. Reference