The Cystic Fibrosis ‘explosion’ – New medicines and unmet needs

Bruce K. Rubin

^{Children’s Hospital of Richmond at Virginia Commonwealth University, 1000 E Broad St, Richmond, VA 23298 USA}

Summary

Cystic fibrosis (CF) is a multi-system illness caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene and protein. CFTR is an ion channel regulating transport of chloride, bicarbonate, and water, and influencing sodium resorption. Advances in CF care have led to dramatic increases in life expectancy and quality of life. We have entered an era of precision medicine, with therapy targeted to modify the CFTR protein, increasing production (premature termination codon read through), preventing degradation in the endoplasmic reticulum, improving folding, and chaperoning to the cell surface (correction), and increasing the open channel probability (potentiation). There are many new entrants into this therapeutic area, including combination therapy to enhance the recovery and effectiveness of ion transport through the most common CF gene defect – phe508del. Challenges for modulator therapies include targeting uncommon CFTR defects, assessing the long term effects of these therapies, and identifying clinical trial outcomes to evaluate the potential for very early therapy of infants with CF.

An additional need is effective immunomodulator therapy that can safely decrease the overwhelming neutrophil dominated inflammation that damages the CF airway. While glucocorticosteroids are effective in suppressing the eosinophil dominant inflammation characteristic of asthma, these appear to have little or no value in treating CF airway inflammation and their use comes at a significant cost in adverse events and current therapies for neutrophil dominant inflammation have limited effectiveness.