Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Innovative therapeutic i

Innovative therapeutic interventions against Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a devastating progressive disease of unknown etiology and is the most lethal form of interstitial lung diseases (ILD). Repeated subclinical injuries to a dysfunctional pulmonary epithelium cause the destruction of the alveolar-capillary basement membrane and a progressive deposition of extracellular matrix (ECM) components, that lead to tissue loss of function. The main role in the process exacerbation is played by Transforming Growth Factor (TGF) that triggers stromal cells (fibroblasts and endothelial) to differentiate into myofibroblasts, which, in turn, produce additional TGF and secrete ECM components Nowadays, the therapeutic approach in IPF and progressive fibrosing ILD seeks the stabilization of fibrotic progression with pirfenidone or nintedanib, but a cure is still lacking. Nintedanib is a tyrosine kinase receptor inhibitor, which interferes with the signaling pathways of TGFβ and other fibrogenic agents, such as the basic Fibroblast Growth Factor (FGF-b) and Platelet Derived Growth Factor (PDGF). Pirfenidone, reduces TGFβ signaling, and the release of chemokines with a still unclear mechanism.

In this scenario, the αvβ6 integrin receptor plays a crucial role in TGFβ activation and recently a small molecule antagonist of αvβ6 integrin receptor entered clinical phase 2 for IPF treatment.

Given the redundancy of the signaling pathways involved in IPF, innovative pharmacological approaches that might target simultaneously different pathways or cellular players are highly attractive.

In the present project, we plan to synthetize new covalent conjugates connecting an αvβ6 integrin ligand, developed by UNIPR RU, with nintedanib or pirfenidone, using either MMPs-cleavable or uncleavable linkers. The integrin ligand is supposed to deliver the conjugates to fibrotic area and inhibit the TGFβ activation.

We are going to investigate the impact of these conjugates as antifibrotic agents in activated fibroblasts recovered from patients, in cultured TGFβ-activated endothelial cells, comparing the activity of the conjugated compounds to simple coadministration of the three active units. Moreover, we will investigate the effect of the conjugated compounds on M2-profibrotic alveolar macrophages recovered from patients. The final goal of the project will be the identification of best combination treatment that inhibit fibrosis in the bleomycin-induced murine model of lung fibrosis to set the foundation for a more efficient anti-fibrotic therapy in IPF and PF-ILDs.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 116034,00

 

Progetto 20225FSFTL finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23021130006