Paris, France, September 25, 2026 – PROTEIN SPECIFIC SIGNATURE OF OTR4132: DOSE EFFECTS Exploring the Antifibrotic Potential of the Heparan Sulfate Mimetic OTR4132 on Validated Human Precision-Cut Lung Slices (hPCLS) Model Mimicking Pulmonary Diseases
Most acute pulmonary injuries are characterized by diffuse alveolar damage (DAD). DAD is an acute nonspecific reaction of the lung, observed commonly in a wide range of infectious diseases (e.g. acute respiratory distress syndrome, SARS-COVID-19), and various other conditions (e.g. xenobiotics, environment, burns). DAD is characterized by scarring and stiffening of lung tissue and may lead to severe loss of lung function such as idiopathic pulmonary fibrosis. DAD causes remodeling of the extracellular matrix (ECM), impairing gas exchange and leading to respiratory distress. In this context, matrix metalloproteinases (MMP) and endoglycanases (e.g. heparanases) are released. MMP mediate the shedding of heparan sulfate (HS) proteoglycans, while heparanases degrade HS chains directly. Together, these processes disrupt the endothelial glycocalyx, impair vascular function, and promote lung edema and neutrophil adhesion.
Some HS mimetics (HSM), known as ReGeneraTing Agents (RGTA®), are synthetic polysaccharides that can promote ECM remodeling by restoring the glycan-based scaffold lost following tissue injury. RGTA® ability to restore the ECM is due to its structural and functional similarities to HS, as well as its resistance to heparanases. In altered ECM, RGTA® bind to growth factors, protecting them from enzymatic degradation and increasing their bioavailability, to promote tissue repair.
To evaluate the effect of this matrix therapy on the slowing of the progression from DAD to lung fibrosis, we used an ex vivo human precision-cut lung slices (hPCLS) model. This model has two key advantages: it preserves the native three-dimensional architecture of the lung and retains all major lung cell types. These characteristics make hPCLS an ideal system for investigating lung diseases and for assessing the safety, efficacy, and toxicity of novel therapies. After confirming that RGTA® OTR4132 was non-toxic in the hPCLS model, the slices were exposed to a profibrotic cocktail (PFC) known to induce a cytokine storm and lead to fibrosis. Three concentrations of OTR4132 were then tested, with nintedanib used as a positive antifibrotic control. Model validation was achieved through histological staining (HE, Alcian blue, MT, PAS), followed by proteomic analysis. Proteomic analysis revealed that PFC induced the upregulation of collagens, proinflammatory cytokines, and proteoglycans, which was attenuated by nintedanib. Not only did OTR4132 modulated these markers, but it also affected proteins involved in ECM remodeling (MMP-1, MMP-9, MMP-12), TGF-β signaling inhibition (BCAR1), and inflammation and angiogenesis (IBP7, ANGP2, VEGFR1). Overall, these results support the antifibrotic activity of OTR4132 in a validated hPCLS model.
Poster FIBER Mariia Pestriakova Final-MP-MP.
