WS10.06Pre-clinical validation of GY971, a new anti-inflammatory agent targeting Nuclear Factor kappa B (NF-kB)

Objectives

Despite the introduction of novel CFTR modulator treatments, the progressive pulmonary damage and lung inflammation hallmarks of cystic fibrosis (CF) continue to persist. Although bacterial infections and inflammatory biomarkers show improvement, they do not fully normalize, highlighting the need for further anti-inflammatory (AI) strategies. Given the severe side effects of chronic AI therapies, such as ibuprofen, which can cause gastrointestinal bleeding, new anti-inflammatory drugs are urgently needed. A key mediator of CF inflammation is the NF-kB transcription factor, which can regulate the expression of pro-inflammatory genes, such as interleukin-8 (IL-8), a significant biomarker of lung inflammation in people with CF (pwCF).

This study outlines the development and characterization of synthetic compounds aimed at modulating the NF-kB activity as a new innovative therapy for CF.

Methods

In the first phase of the research, we focused on the analysis of various synthetic derivatives in CF bronchial epithelial cell lines exposed to Pseudomonas aeruginosa (Pa) or TNF-alpha in vitro and in mouse models of Pa lung infection in vivo.

Results

The new furocoumarin derivative GY971 proved to be the best derivative identified in this screening, and it demonstrated promising anti-inflammatory effects, both in vitro and in vivo, providing a foundation for further investigations. In the second phase of our study, the anti-inflammatory effects of GY971 were also validated in primary HBE (Human Bronchial Epithelial cells) derived from pwCF without any genotoxic or phototoxic effects.

Conclusion

Thanks to the promising results, GY971 was recently approved by the European Medicines Agency (EMA) as an orphan drug for CF. Our ongoing research aims to consolidate its efficacy and safety profile, bringing it closer to clinical application as an innovative AI treatment for CF lung disease.