Lessons from other fields of medicine, Part 2: Cystic fibrosis.

Cystic fibrosis (CF), first described in 1938, is a common, life-limiting monogenetic disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 was crucial in advancing our understanding of disease pathogenesis and paving the road for treatment aimed at the fundamental molecular defect. With the delineation of over 2000 variations in the CFTR gene, a sound understanding of the individual variations in cell biology, and electrophysiological abnormalities conferred by the most common defects propelled the advent of targeted disease-modifying therapeutics beginning in 2012. Since then, CF care has transformed beyond just symptomatic treatment to include a variety of small-molecule therapies that address the basic electrophysiologic defect and cause profound improvements in physiology, clinical manifestations, and long-term outcomes, designed to differentially address six genetic/molecular subtypes. This chapter illustrates the progress made toward how fundamental science and translational initiatives enabled personalized, mutation specific treatment. We highlight the importance of preclinical assays and mechanistically-driven development strategies that were coupled with sensitive biomarkers and a clinical trial cooperative to provide a platform for successful drug development. This convergence of academic and private partnerships, and formation of multidisciplinary care teams directed by evidence-based initiatives provide a seminal example of addressing the needs of individuals with a rare, but fatal genetic disease.