Periodic Reporting for period 2 - Pulmonary Fibrosis (Glycomic and Genomic Repercussion of Nebulisable Gal-3 Inhibitory Medical Device Treatment in Pulmonary Fibrosis)
Berichtszeitraum: 2024-09-01 bis 2025-08-31
Idiopathic pulmonary fibrosis (IPF) is the most common of idiopathic interstitial pneumonia with an increasing prevalence due to aged population, lifestyle and environmental exposure [1]. Today there is no cure for IPF, there is only two approved treatments that slow down progression. There is a need for new and more efficient anti-fibrotic treatments that stop and resolve fibrosis in IPF. In the current project, we were exploring the conjugation of a novel anti-fibrotic drug (TD139) to macromolecular polyethylene glycol (PEG) through a cleavable link to improve nebulization delivery, alveolar retention and prolonged delivery of TD139. Unfortunately, TD139 was discontinued from Phase II clinical trials do to worsening of effects [2].
This project has optimized the chemical functionalization and conjugation of galectin-3 inhibitor TD139 to water soluble macromolecular polyethylene glycol to allow high dose nebulization as means of direct, efficient and gentle alveolar delivery while promoting retention and sustained delivery of functionally active TD139 through spontaneous cleavage bond at different speeds. This project has optimized in vitro models to test the galectin-3 inhibitory potential of the released TD139. This project has optimized in vitro and in vivo models to validate the anti-fibrotic potential of TD139. Despite TD39 efficiently inhibiting the carbohydrate binding of Galectin-3 it failed to decrease the pro-fibrotic effects induced in vitro and in vivo which is in contrast with previous published studies but aligns with discontinuation of TD139 clinical trial for pulmonary fibrosis due to unmet results. The inefficacy of TD139 to mitigate fibrosis has resulted in the absence of implementation of the genomic and glycomic studies proposed in this study. A publication is under preparation for Bioconjugates Journal.
As a side project, I validated a novel rapid and efficient method to differentiate idiopathic pulmonary fibrosis (IPF) from other interstitial lung disease (ILD) biopsies applying Raman spectroscopy and big data analysis. We were able to classify IPF from other ILD biopsies in a small cohort using linear mixed effects model and Principal Component Analysis with positive outcomes. The diagnosis of IPF is challenging and delays treatment implementation, there is a need of supporting diagnostic tools. A publication is under final senior authors revision to submission to the European Respiratory Journal.
As a second side project, I developed a method to eliminate agarose carryover contamination during RNA extraction for PCLS that significantly hindered validation studies in the secondment institution. Removal or agarose leads to high integrity yield RNA extractions allowing efficient readouts. A publication with me as senior author is under preparation to submission to the Red Pulmonary Journal.
I have been involved in a external collaboration with the secondment institution and the University of California San Diego (UCSD) to characterize microplastics in lung tissue. Increasing mass plastic pollution accumulates affecting air quality. Airborne microplastics are a concern for human health and often overlooked due to difficulties in detecting them. We are able to quantify amount in tissue samples and spatially spot the in histological sections by epifluoresence and Raman Spectroscopy. Transcriptomic studies are on going. We are planning a publication me being the lead author.
This project has optimized the chemical functionalization and conjugation of galectin-3 inhibitor TD139 to water soluble macromolecular polyethylene glycol to allow high dose nebulization as means of direct, efficient and gentle alveolar delivery while promoting retention and sustained delivery of functionally active TD139 through spontaneous cleavage bond at different speeds. This project has optimized in vitro models to test the galectin-3 inhibitory potential of the released TD139. This project has optimized in vitro and in vivo models to validate the anti-fibrotic potential of TD139. Despite TD39 efficiently inhibiting the carbohydrate binding of Galectin-3 it failed to decrease the pro-fibrotic effects induced in vitro and in vivo which is in contrast with previous published studies but aligns with discontinuation of TD139 clinical trial for pulmonary fibrosis due to unmet results. The inefficacy of TD139 to mitigate fibrosis has resulted in the absence of implementation of the genomic and glycomic studies proposed in this study. A publication is under preparation for Bioconjugates Journal.
As a side project, I validated a novel rapid and efficient method to differentiate idiopathic pulmonary fibrosis (IPF) from other interstitial lung disease (ILD) biopsies applying Raman spectroscopy and big data analysis. We were able to classify IPF from other ILD biopsies in a small cohort using linear mixed effects model and Principal Component Analysis with positive outcomes. The diagnosis of IPF is challenging and delays treatment implementation, there is a need of supporting diagnostic tools. A publication is under final senior authors revision to submission to the European Respiratory Journal.
As a second side project, I developed a method to eliminate agarose carryover contamination during RNA extraction for PCLS that significantly hindered validation studies in the secondment institution. Removal or agarose leads to high integrity yield RNA extractions allowing efficient readouts. A publication with me as senior author is under preparation to submission to the Red Pulmonary Journal.
I have been involved in a external collaboration with the secondment institution and the University of California San Diego (UCSD) to characterize microplastics in lung tissue. Increasing mass plastic pollution accumulates affecting air quality. Airborne microplastics are a concern for human health and often overlooked due to difficulties in detecting them. We are able to quantify amount in tissue samples and spatially spot the in histological sections by epifluoresence and Raman Spectroscopy. Transcriptomic studies are on going. We are planning a publication me being the lead author.
We have optimized and validated the covalent conjugation of TD139 to PEG with two cleavable moieties that allow spontaneous release of TD139 in its original form ranging from a few days to a couple of months under physiological conditions. The PEG-TD139 conjugates are soluble and can be nebulized.
We have tested the anti-fibrotic effect of TD139 in different in vitro, mice and human precision cut lung slices and mice in vivo models to validate the efficiency of the conjugates. Unfortunately, any of these models have shown a remarkable anti-fibrotic effect which is in line with the current discontinuation of TD139 from clinical trials. We are exploring the conjugation of sobetirome, another novel anti-fibrotic drug, which anti-fibrotic effects have been tested in the secondment institution.
Parallelly, I have been involved in the validation of Raman spectroscopy for the diagnosis of IPF among patients with interstitial lung disease (ILD). The diagnosis of IPF is complex, unprecise and time-consuming. Raman spectroscopy is sensitive to molecular changes and can be used to classify different tissue states [4]. Using big data processing and discriminant analysis we have been able to predict IPF and non-IPF outcome in a small cohort of IPF and non-IPF ILD samples with a decent accuracy. We are working in the inclusion of more measurements to improve the accuracy of the analysis.
I developed a method to eliminate agarose carryover contamination during RNA extraction for PCLS that significantly hindered validation studies in the secondment institution. Removal or agarose leads to high integrity yield RNA extractions allowing efficient readouts.
I have been involved in a external collaboration with the secondment institution and the University of California San Diego (UCSD) to characterize microplastics in lung tissue. Increasing mass plastic pollution accumulates affecting air quality. Airborne microplastics are a concern for human health and often overlooked due to difficulties in detecting them. We are able to quantify amount in tissue samples and spatially spot the in histological sections by epifluoresence and Raman Spectroscopy. Transcriptomic studies are on going.
[4] j.actbio.2023.03.016 [5] ajplung.00084.2017
We have tested the anti-fibrotic effect of TD139 in different in vitro, mice and human precision cut lung slices and mice in vivo models to validate the efficiency of the conjugates. Unfortunately, any of these models have shown a remarkable anti-fibrotic effect which is in line with the current discontinuation of TD139 from clinical trials. We are exploring the conjugation of sobetirome, another novel anti-fibrotic drug, which anti-fibrotic effects have been tested in the secondment institution.
Parallelly, I have been involved in the validation of Raman spectroscopy for the diagnosis of IPF among patients with interstitial lung disease (ILD). The diagnosis of IPF is complex, unprecise and time-consuming. Raman spectroscopy is sensitive to molecular changes and can be used to classify different tissue states [4]. Using big data processing and discriminant analysis we have been able to predict IPF and non-IPF outcome in a small cohort of IPF and non-IPF ILD samples with a decent accuracy. We are working in the inclusion of more measurements to improve the accuracy of the analysis.
I developed a method to eliminate agarose carryover contamination during RNA extraction for PCLS that significantly hindered validation studies in the secondment institution. Removal or agarose leads to high integrity yield RNA extractions allowing efficient readouts.
I have been involved in a external collaboration with the secondment institution and the University of California San Diego (UCSD) to characterize microplastics in lung tissue. Increasing mass plastic pollution accumulates affecting air quality. Airborne microplastics are a concern for human health and often overlooked due to difficulties in detecting them. We are able to quantify amount in tissue samples and spatially spot the in histological sections by epifluoresence and Raman Spectroscopy. Transcriptomic studies are on going.
[4] j.actbio.2023.03.016 [5] ajplung.00084.2017
This project has provided me with excellent knowledge and training about competitive methodologies like PCLS experimentation, sequencing interpretation, potential mechanisms for lung injury treatment and excellent contacts within the academia and industry in the field of pulmonary biology. This has allowed me to secure a faculty position as Research Scientist at Yale University in the secondment laboratory to continue testing potential mechanistic pathways of interest in human PCLS for drug discovery. The work carried out creates market opportunities in the field of treatment discovery and diagnosis of pulmonary fibrosis that can be exploit by companies and the clinics. My collaborative involvement in addressing microplastics in lung has an impact in how technology development has an impact in climate change and human health. Innovation activities involve collaboration within industry projects to test novel developed drugs in human PCLS to support clinical studies. The work carried out in this gran contributes towards the objective of a better quality live for all in the field of respiratory health in terms of improving treatments and more efficient diagnostic tools. Potential users of the technology developed are biomedical applications were the sustained inhibition of galectin-3 is beneficial, drug delivery of insoluble small drugs, clinicians working in the diagnosis of IPF, companies interested in drug validation in human pulmonary samples.