Author: Claire Hornung

Translational Science in Pulmonary Fibrosis

Posted on by Claire Hornung

Watch “Translational Science in Pulmonary Fibrosis: From patients to cells and back—increasing success in drug development,” to learn more about what drives pulmonary fibrosis, with insights from machine learning and translational biomarkers.

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Agenda

  • Introduction
  • Leveraging machine learning for patient stratification and advanced analytics – a COPD case study | Line Egerod
  • Investigating fibrosis mechanisms – what drives fibrosis in the lungs? | Dr. Naftali Kaminski
  • Utilizing translational biomarkers for drug development in fibrotic lung diseases | Dr. Federica Genovese
  • Roundtable discussion and Q&A

Scientific topics and speakers

The session will begin with an investigation into the mechanisms driving lung fibrosis, examining key processes that underlie this progressive condition. We will then delve into the role of machine learning in pulmonary research, highlighting its application for patient stratification and advanced analytics through a COPD case study.

Finally, discussions will focus on the use of translational biomarkers in drug development, offering insights into more targeted and effective therapies. This webinar is designed for researchers, clinicians, and industry professionals interested in the latest translational strategies for tackling pulmonary fibrosis.

Dr. Naftali Kaminski

  • Dr. Naftali Kaminski is the Boehringer-Ingelheim Endowed Professor of Internal Medicine and Chief of Pulmonary, Critical Care, and Sleep Medicine at Yale School of Medicine since 2013, with prior leadership at the University of Pittsburgh.
  • He is a global leader in genomic research for chronic lung diseases, including Idiopathic Pulmonary Fibrosis (IPF), COPD, severe asthma, and sarcoidosis, pioneering transcript profiling and omics integration for precision medicine.
  • Dr. Kaminski’s research has identified novel therapeutic targets in IPF, such as metalloproteases (MMP7, MMP19), phosphatases (SHP2, MKP5), and antifibrotic roles for thyroid hormone signaling. His team’s discoveries include the role of microRNAs (e.g., let-7, mir-29, mir-33) in lung fibrosis and the development of predictive blood-based biomarkers for IPF risk stratification and transplant prioritization.
  • Dr. Kaminski has authored more than 340 peer-reviewed publications in top journals, including Nature Medicine, NEJM, Science Translational Medicine, and Lancet Respiratory Medicine, while consistently securing NIH funding since 2000.
  • Recognized for his contributions to pulmonary research, he received awards such as the Marvin I. Schwarz Award (2010), the ERS Gold Medal for ILD (2016), and the ATS Amberson Lecture Award (2022), among many others. He is a Fellow of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) and has served in leadership roles within ATS, including as Chair of the Assembly on Respiratory Cell and Molecular Biology.
  • Dr. Kaminski is passionate about training the next generation of physician-scientists in genomics, bioinformatics, and systems biology, mentoring numerous successful MDs and PhDs in launching independent, well-funded careers. He continues to influence clinical and translational lung disease research as an associate editor for Thorax, BMJ, and through leadership in pulmonary genomic medicine.

Dr. Federica Genovese

  • Dr. Federica Genovese is the Director of Cardiovascular and Renal (CVR) Research at Nordic Bioscience. She also heads the Translational Research group.
  • She joined Nordic Bioscience in 2011 and assumed the role of Group leader of Kidney research in 2015 and then became Director of CVR in 2019.
  • Dr. Genovese focuses on developing serologically assessed markers to evaluate extracellular matrix remodeling in patients with cardiovascular and renal diseases, aiding in prognostic and pharmacodynamic evaluation.
  • Her team has produced the bulk of data on endotrophin, measured by the PRO-C6 assay, a fibroblast activity marker and a pro-fibrotic molecule, utilized as risk marker of adverse outcomes in multiple fibro-inflammatory diseases.
  • Dr. Genovese has authored more than 100 peer-reviewed publications, demonstrating her extensive contributions to the field.
  • Her H-index is 28, her I10-index is 42, and her research has garnered over 3400 citations as of November 2024.

Line Egerod

  • Line Egerod is a PhD student in the Hepatic and Pulmonary Research Team at Nordic Bioscience based in Copenhagen.
  • Before joining Nordic Bioscience in 2022, she worked as a machine learning engineer in Oxford, UK, and Silicon Valley, CA, US, gaining experience across various disease areas.
  • She is the main data steward for the ECLIPSE cohort, one of the largest and most comprehensive COPD studies to date.
  • Her research focuses on using interpretable machine learning models alongside inflammation and extracellular matrix biomarkers to uncover opportunities for patient stratification and personalized profiling in COPD.
  • Working closely with pharmaceutical companies worldwide, she and her colleagues have supported clinical research that has contributed to multiple clinical studies and publications in high-ranking scientific journals.
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    Tocilizumab Superior to Methotrexate in Collagen Degradation Inhibition

    Posted on by Claire Hornung

    Tocilizumab demonstrates superior inhibition of MMP-mediated basement membrane collagen degradation compared to methotrexate or placebo

    Introduction

    Rheumatoid arthritis (RA) pathogenesis involves a range of immune cells, for instance T-cells, neutrophils and macrophages. They produce proinflammatory factors, such as proteolytic enzymes, which interact with tissue components such as collagens, leading to a release of unique tissue fragments into the circulation. Type IV collagen is a basement membrane supporting endothelium and epithelium. From previous studies, we know that T-cell activity may be quantified by measuring C4G, a metabolite of Granzyme B (a cytotoxic granule enzyme) mediated degradation of type IV collagen, while C4M is a marker of MMP activity. Quantifying these unique metabolites reflecting the interaction between immune cell and type IV collagen may provide a deeper understanding of the tissues affected by RA and be more relevant to disease activity and progression than simply quantifying the immune cell number or cytokines.

    The aim of this study was to investigate the association between the unique immune cell activity metabolites C4G and C4M, and clinical outcomes in RA before and after intervention with tocilizumab, methotrexate (MTX) and placebo.

    Poster

    ACR2024 Type IV collagen in RA_Nordic BioscienceDownload

    Conclusion

    Type IV collagen is a basement membrane protein important for tissue integrity. It is degraded during RA
    leading to a destabilized tissue. The two biomarkers studied, C4G and C4M, were differentially associated with clinical outcome measures. Importantly, only C4M, a marker of MMP-derived tissue destruction, could be inhibited by tocilizumab. None of the markers were modulated by MTX.

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      α-synuclein—a critical protein in Parkinson’s disease

      Posted on by Claire Hornung

      Understanding Parkinson’s Disease Progression Through Protein Biomarkers

      Parkinson’s Disease (PD) is a complex neurodegenerative disorder, primarily affecting the brain’s control over movement, thought, memory, and emotion. Early symptoms often manifest as tremors due to impaired motor skills. Underlying these visible symptoms is a cascade of molecular changes, beginning with alterations in specific proteins—one of which, α-synuclein, plays a critical role in PD pathology. In Figure 1, we have illustrated how α-Synuclein aggregates, which impairs the motor neuron.

      Figure 1. Patients diagnosed with Parkinson’s Disease is affected by A) α-Synuclein aggregates affecting the motor neurons, B) Neuron loss and degeneration, and C) Blood-Brain-Barrier (BBB) leakage and neuroinflammation, by activated microglia, reactive astrocytes and extracellular matrix destruction.

      In a healthy brain, α-synuclein supports neuronal communication. However, in Parkinson’s, this protein undergoes abnormal processing, driven partly by the enzyme Calpain-1, which cleaves α-synuclein into smaller, altered fragments. This early cleavage disrupts cellular function and promotes the formation of toxic aggregates, which accumulate, kill neurons, and drive disease progression. Intriguingly, these fragmented proteins can cross the blood-brain barrier and enter the bloodstream, providing a potential “window into the brain” for tracking disease activity from a simple blood sample.

      At Nordic Bioscience, we have developed an innovative approach to harness this biomarker potential. Using our ProteinFingerPrint Biomarker Technology™, we can detect Calpain-1-cleaved α-synuclein fragments in blood serum with high precision. Our specific assay, α-SYN-C, captures the unique “fragment fingerprint” of PD by quantifying these cleaved fragments, which are significantly elevated in the blood of PD patients compared to healthy individuals, as illustrated in Figure 2.

      Figure 2. Patients with Parkinson’s Disease has significant higher levels of α-SYN-C in serum, compared to healthy donors. The α-SYN-C biomarker detects levels of α-Synuclein cleaved by Calpain-1 in serum. The assay is technically validated for measurements in human blood samples.

      This biomarker offers a non-invasive, accessible tool for monitoring Parkinson’s Disease progression and evaluating therapeutic responses. By examining α-SYN-C levels in blood samples, our technology not only provides insights into PD mechanisms but also opens doors for developing targeted therapies that address the disease’s underlying pathology. Through this work, we aim to support more accurate PD diagnostics and more effective, individualized treatments in the fight against neurodegeneration.

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        FAP-Activity Is Associated with Survival Outcomes in Patients with PDAC

        Posted on by Claire Hornung

        Fibroblast Activation Protein (FAP) generates a specific type III collagen fragment detectable in serum, which is associated with survival outcomes in patients with PDAC

        Introduction

        FAP expression is very low in healthy tissues, and highly upregulated in tumors Fibroblast activation protein (FAP) has unique proteolytic activity. The disease specific expression and unique proteolytic activity have made FAP an interesting protein to be utilized for drug targeting purposes. Therefore, it is important to identify the patients with FAP activity.

        In this study we aimed to measure FAP activity indirectly through its proteolytic degradation of type III collagen in serum from patients with PDAC and evaluate its prognostic value.

        Poster

        SITC2024 FAP in PDAC patients_Nordic BioscienceDownload

        Conclusion

        FAP-activity can be assessed non-invasively through quantification of FAP-cleaved type III collagen and is
        associated with survival outcome in patients with PDAC.

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          Circulating NordicEndotrophin™ is an Early Marker of Kidney Disease Development in T2D

          Posted on by Claire Hornung

          Circulating endotrophin is an early marker of kidney disease development in persons with type 2 diabetes

          Introduction

          NordicEndotrophin™ (Endotrophin), a pro-fibrotic fragment generated during collagen type VI formation, measured by nordicPRO-C6™, has been largely investigated as a biomarker of adverse outcome in persons with diabetic kidney disease. We investigated its potential to predict kidney disease onset in two independent type 2 diabetes (T2D) cohorts.

          Poster

          ASN2024 PRO-C6 T2D_Nordic BioscienceDownload

          Conclusion

          Circulating nordicEndotrophin™, measured by the nordicPRO-C6™ assay, was a risk marker for kidney outcomes in people with T2D without or with early kidney disease. This adds to the evidence that nordicEndotrophin™is a relevant biomarker of kidney complications in T2D, even in persons with no or mild kidney disease at baseline.

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            Validating NordicEndotrophin™ as a Risk Marker of Complications in Type 2 Diabetes

            Posted on by Claire Hornung

            Development of a novel assay to quantify circulating full-length endotrophin and validation as a risk marker of complications in T2D

            Introduction

            NordicEndotrophin™ (ETP), a bioactive fragment of type VI collagen (COL6), has been widely evaluated as a biomarker of risk of outcome in type 2 diabetes (T2D). The most used assay to quantify ETP is a competitive ELISA employing an antibody targeting the C-terminal of the α3 chain of COL6, encompassing part of the ETP sequence (nordicPRO-C6™).

            We developed a sandwich ELISA targeting full-lenght ETP (nordicEndotrophin™), which employes an antibody targeting the N-terminal end of the ETP molecule and the antibody targeting the C-terminal end of COL6A3 (nordicPRO-C6™). We evaluated the potential of the two assays as risk markers of T2D adverse outcomes.

            Poster

            ASN2024 Full Lenght Endotrophin_Nordic BioscienceDownload

            Conclusion

            The nordicEndotrophin™ assay is a technically robust sandwich ELISA quantifying the full-lenght endotrophin molecule in circulation. This biomarker presents a similar, or possibly higher prognostic power for complications of T2D than the competitive ELISA nordicPRO-C6™, used so far to quantify nordicEndotrophin™ in circulation.

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              Activated Macrophage-Conditioned Media Induces Fibrogenesis in a Scar-in-a-Jar Model

              Posted on by Claire Hornung

              Activated macrophage-conditioned media induces fibrogenesis in a gastrointestinal scar-in-a-jar model that is quantifiable with serological biomarkers of collagen formation

              Introduction

              Intestinal fibrosis affects most inflammatory bowel disease (IBD) patients, resulting in severe clinical complications and reduced treatment response. Driven primarily by myofibroblasts, this condition is characterized by the excessive accumulation of extracellular matrix in the intestines. With no treatments approved for intestinal fibrosis, there is a need for preclinical models to investigate the pathobiology and novel treatments.

              In this study we investigated the profibrotic effects of activated macrophages (Mφ) in a scar-in-a-jar
              model of colonic fibrogenesis using validated protein fingerprint assay (PFA) biomarkers of collagen formation.

              Poster

              UEG2024 Gastrointestinal Scar-in-a-jar model_Nordic BioscienceDownload

              Conclusion

              The noninvasive PFA biomarkers can be used to objectively quantify fibrogenesis in the in vitro Scar-in-a-Jar model, providing a valuable tool for investigating the underlying mechanisms of fibrogenesis.

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                Type IV Collagen Alpha-3 Chain Degradation Is Linked to Treatment and Pulmonary Hypertension in IPF

                Posted on by Claire Hornung

                Degradation of the alveolar basement membrane type IV collagen alpha-3 chain is associated with antifibrotic treatment and pulmonary hypertension in idiopathic pulmonary fibrosis

                Introduction

                Idiopathic pulmonary fibrosis (IPF) is a rare but devastating disease with inevitable progression and high mortality. Currently, Pirfenidone and Nintedanib are the only approved antifibrotic treatment options to slow disease progression. Additionally, a pulmonary hypertension (PH) complication can further worsen disease outcome and quality of life. Forced vital capacity (FVC) is currently the most employed endpoint in clinical trials to monitor disease progression for antifibrotic treatment (Tx) development.

                Molecularly, the extracellular matrix is subjected to excessive, pathological remodeling during IPF progression. Type IV collagen (COL4) is a critical part of the basement membrane that support the epithelium and crucial to cellular integrity. Mature COL4 are trimers that can be derived from six different alpha-chains, wherein the a3-chain is predominantly expressed in alveoli. Other trimers are expressed ubiquitously.

                The aim was to investigate potential associations with antifibrotic Tx and PH in IPF patients by comparing serological levels of alveolar basement membrane degradation by a fragment of the COL4 alpha-3 chain (C4Ma3) with a fragment of more general remodeling by the alpha-1 chain (PRO-C4).

                Poster

                ICLAF2024 Type IV Collagen Alpha-3 Chain_Nordic BioscienceDownload

                Conclusion

                The COL4 alpha-3 chain has limited tissue distribution and is crucial for alveolar function. In this study, higher levels of COL4 alpha-3 chain degradation (C4Ma3) was:

                • found in IPF with PH.
                • associated with no antifibrotic treatment, indicating a pharmacodynamic potential.

                In comparison, the COL4 alpha-1 chain marker PRO-C4, indicating ubiquitous basement membrane remodeling, did not show statistically different levels between any of the groups compared in this study. This could highlight the fact that damage done within alveoli are especially relevant when assessing the effect of antifibrotic Tx and PH in IPF.  

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                  Results from the Phase IIb RECITAL Trial

                  Posted on by Claire Hornung

                  Reduction of PRO-C3 and PRO-C6 fibrogenesis biomarkers in connective tissue disease-associated interstitial lung disease: results from the Phase IIb RECITAL trial

                  Introduction

                  Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue disease (CTD). While cyclophosphamide is often an effective treatment for CTD-ILD, its use is limited by side effects.

                  In this study, Rituximab was tested as an alternative in the RECITAL phase IIb trial (NTC1862926). Both drugs improved 24- and 48-week lung function with rituximab showing fewer adverse events.

                  Poster

                  ICLAF2024 Phase IIb RECITAL Trial_Nordic BioscienceDownload

                  Conclusion

                  The decrease in nordicPRO-C6™ and nordicPRO-C3™ suggest that, besides their immunomodulatory effects, these drugs may also reduce fibrogenesis. NordicPRO-C3™ and nordicPRO-C6™, measured at baseline and as % change from baseline, are associated with an FVC response. These findings highlight nordicPRO-C3™ and nordicPRO-C6™ as promising biomarkers for CTD-ILD.

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                    C1SIG Predicts All-Cause Mortality at Admission with STEMI

                    Posted on by Claire Hornung

                    A novel serological biomarker targeting a collagen type-I-derived matricryptin predicts all-cause mortality at admission with ST-elevated myocardial infarction

                    Introduction

                    ST-elevated myocardial infarction (STEMI) damages local cardiac tissue and leads to acute inflammation-driven tissue remodeling immediately after injury. A collagen type I (COL1) matricryptin cleaved by MMP-2 and MMP-9 was previously identified as being involved in left ventricular remodeling after a MI.

                    We aimed to develop, technically evaluate, and quantify this COL1- derived matricryptin, named C1SIG, as a serological biomarker in a clinical cohort of STEMI patients.

                    Poster

                    MBE2024_C1SIG in STEMI_Nordic BioscienceDownload

                    Conclusion

                    C1SIG was developed as a technically robust biomarker and demonstrated as an independent predictor of
                    mortality at 30 days and 1-year after STEMI, even when adjusted for multiple clinically-relevant variables.
                    This COL1 biomarker could be helpful in assessing acute extracellular matrix processing in individuals after suffering a STEMI and could identify a subset of patients at increased risk of long-term outcome.

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