A peptide targeting p21-CDK4 interaction for treatment of pulmonary fibrosis

Description du projet

Un nouveau traitement de la fibrose pulmonaire

La fibrose pulmonaire est une maladie pulmonaire mortelle qui affecte des millions de personnes dans le monde. Elle se caractérise par une cicatrisation progressive et une altération de la respiration. Les traitements actuels ralentissent la progression, mais ne peuvent inverser les dommages ni étendre la survie. L’accumulation de cellules âgées et dysfonctionnelles, appelées cellules sénescentes, qui résistent à la mort et favorisent la formation de cicatrices, est un facteur clé de la fibrose. Le projet FibroPep, financé par le CER, cible une interaction récemment découverte entre deux protéines (p21 et CDK4) qui est essentielle à la survie des cellules sénescentes et à la formation du tissu cicatriciel. Des peptides synthétiques spécialement conçus perturbent cette interaction et éliminent de manière sélective les cellules sénescentes dans des modèles précliniques. Le projet va à présent identifier un peptide thérapeutique principal et valider son efficacité, jetant ainsi les bases d’un potentiel traitement curatif.

Objectif

Pulmonary fibrosis is an age-related disease characterized by progressive scarring of lung tissue, loss of respiratory function, and premature death. It is a fatal disease, affecting roughly ~5 million worldwide and causing >17.000 annual deaths in Europe alone. There is no cure for pulmonary fibrosis, as current treatments modestly slow disease progression but do not reverse fibrosis or substantially improve survival. These therapies often carry significant side effects and fail to address the underlying drivers of the disease, namely, the accumulation of senescent cells and ECM production. To meet this urgent unmet medical need, we propose a novel therapeutic strategy that selectively targets a key protein-protein interaction driving fibrosis.
We discovered that the interaction between p21 and CDK4 is critical for both the survival of senescent cells and the regulation of ECM components. Disrupting this interaction mimics the effects of p21 knockdown, which we have shown eliminates senescent cells and limits fibrosis. Based on this insight, we designed and tested synthetic peptides that bind to CDK4 and block its interaction with p21. Several of these peptides show strong binding and selective senolytic activity in vitro, demonstrating precise modulation of this novel target and offering a promising strategy for an incurable disease.
Our PoC project will advance this innovation toward therapeutic application. Specifically, we aim to identify a lead peptide with low micromolar potency and test its efficacy in a preclinical mouse model of pulmonary fibrosis, thereby reaching TRL4. This work lays the foundation for a highly specific, well-tolerated, and potentially curative treatment that addresses the root mechanisms of fibrosis rather than its symptoms alone. By targeting a previously unexplored molecular pathway, our approach offers new hope for millions affected by fibrotic lung diseases and could extend to broader applications in age-related fibrotic conditions.