Rethinking inhaled therapies for pulmonary fibrosis
Idiopathic pulmonary fibrosis(opens in new window) (IPF) is a progressive and ultimately fatal lung disease characterised by excessive scarring of lung tissue. Its prevalence is rising, driven by ageing populations, environmental exposure and lifestyle factors. Despite major clinical efforts, there is currently no cure, and the two approved therapies only slow disease progression. This unmet medical need has fuelled interest in novel targets and delivery strategies that could improve therapeutic outcomes.
A new target for fibrosis
Undertaken with the support of the Marie Skłodowska-Curie Actions(opens in new window) programme, the Pulmonary Fibrosis project focused on galectin-3(opens in new window) (Gal-3), a carbohydrate-binding protein increasingly linked to fibrotic disease. Preclinical evidence has shown that Gal-3 promotes fibrosis by stabilising and enhancing tissue scarring. “Galectin-3 emerged as an attractive therapeutic target because of its central role in amplifying profibrotic signalling,” explains principal investigator Joan Martí Muñoz. The team selected TD139, a small carbohydrate-based Gal-3 inhibitor that had already entered clinical trials for IPF. However, like many inhaled drugs, TD139 is rapidly cleared from the lungs. To address this, the researchers explored biomaterials for drug delivery, conjugating TD139 to macromolecules such as polyethylene glycol (PEG) and hyaluronic acid with chemical linkers.
Prolonging drug retention in the lung
The rationale behind the approach was to increase retention and sustain the biological activity of TD139 in the lung over time. In this context, researchers altered the degradability of the chemical linkers, thereby controlling TD139 release from a few weeks up to two months under physiological conditions. “This strategy allowed us to modulate drug delivery kinetics while maintaining the biological activity of the released compound,” states Martí Muñoz. An additional benefit of the conjugation strategy was improved solubility. TD139 exhibits poor solubility, limiting the dose that can be delivered by inhalation. Conjugation to PEG significantly enhanced solubility, enabling efficient nebulisation of higher drug doses and opening new possibilities for aerosol-based delivery.
Preclinical testing
The research team evaluated the antifibrotic potential of TD139 conjugates using a broad panel of models, including in vitro assays, mouse models and human lung biopsies. While Gal-3 inhibition was confirmed in vitro, the conjugates did not show a marked antifibrotic effect in vivo. These findings align with the discontinuation of TD139 from phase II clinical trials due to lack of clinical benefit. “Negative results are an essential part of scientific progress,” notes Martí Muñoz. “They allow us to refine our hypotheses and redirect efforts toward more promising avenues.”
Beyond therapeutics: diagnostics and models
The project’s impact extends beyond drug delivery. The team has also advanced a novel diagnostic approach for IPF capable of detecting subtle molecular changes in lung tissue. This method has shown promising accuracy in distinguishing IPF from other interstitial lung diseases, paving the way for improved diagnosis and treatment decisions. Project partners also refined an innovative ex vivo lung model based on precision-cut lung slices. This model offers a powerful new tool to study early fibrotic events and aberrant cell populations in human lung tissue. Through their robust chemical functionalisation platform, the Pulmonary Fibrosis team aims to extend future research efforts to other carbohydrate-based drugs. “By combining different tools and data-driven diagnostics, we move closer to designing interventions for pulmonary fibrosis,” concludes Martí Muñoz.
