How Effectively Can Oxidative Stress and Inflammation Be Reversed When CFTR Function Is Pharmacologically Improved?

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Pharmacology

Background:

• Cystic fibrosis (CF) treatment advances include modulator therapies like elexacaftor-tezacaftor-ivacaftor (ETI).
• ETI partially restores CFTR function in individuals with at least one F508del mutation.
• While ETI reduces pathogen load and inflammation, residual oxidative stress and inflammation persist.

Purpose of the Study:

• To investigate the persistent oxidative stress and inflammation in cystic fibrosis patients despite modulator therapy.
• To explore the potential of multi-omics technologies in understanding these persistent pathways.
• To identify novel therapeutic targets for restoring airway health.

Main Methods:

• Analysis of gene expression, epigenetic modifications, protein profiles, and metabolic processes.
• Utilizing airway-derived samples from patients undergoing ETI therapy.
• Employing emerging multi-omics technologies.

Main Results:

• ETI therapy partially restores CFTR function to approximately 50% of normal levels.
• Significant reductions in sputum pathogen content, enhanced microbiome diversity, and lowered inflammation markers observed.
• Persistent residual airway infection, oxidative stress, and inflammation remain, comparable to non-CF bronchiectasis.

Conclusions:

• Partial CFTR function restoration via ETI therapy offers clinical benefits but does not fully resolve oxidative stress and inflammation.
• Innovative antioxidant and anti-inflammatory strategies are crucial, especially for advanced cystic fibrosis lung disease.
• Multi-omics approaches hold promise for elucidating mechanisms of persistent pathology and identifying new therapeutic targets.