ABSTRACT
In the years immediately following the description of cystic fibrosis (CF) as a clinical entity, treatment focused on mitigating the signs and symptoms of disease. In spite of these therapies, the prognosis for people with CF (pwCF) was poor; the majority of individuals experienced death from respiratory failure in childhood or early adulthood. Following discovery of the CF transmembrane conductance regulator (CFTR) gene in 1989, it was hoped that a cure for CF through the development of gene therapy would be imminent. Unfortunately, early trials did not demonstrate clinical efficacy and revealed that additional knowledge was needed to ensure the safety of gene therapy. Investigators subsequently focused on the development of small molecule therapy to improve the quantity and function of the CFTR protein at the cell surface. To date, four therapies have been approved to impact the basic defect for those with responsive variants. While the majority of pwCF (>90%) have variants that could be treated with CFTR modulators, variant ineligibility, drug intolerance and lack of access prevent many pwCF from benefiting. Individuals who identify as Black, Indigenous and people of color are overrepresented in the group of pwCF not benefiting from CFTR modulators.
For those eligible for CFTR modulators, this chapter reviews the clinically relevant respiratory effects of approved therapies with consideration of factors impacting variable response and future development of new therapies.
