Cystic Fibrosis Therapy: From Chest Physiotherapy to Agents Targeting Specific Mutations

Abstract

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder that was a terminal illness in young children. Standardized care in accredited CF Centers and medical advances in maintenance medications targeting nutritional health, CF bacterial pathogens, inflammation, mucociliary clearance, and the underlying defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, improved life expectancy and quality of life for people with CF [1,2]. Today, half of the United States CF population is of adult age. According to the 2018 Cystic Fibrosis Foundation (CFF) Patient Registry, 54.6% were 18 years and older [3]. The life expectancy of people with CF born between 2014 and 2018 is predicted to be 44.4 years (95 percent confidence interval: 43.4-45.9 years) [3,4].The discovery of the CFTR gene 1989 triggered a a surge in basic research [5]. While this enhanced knowledge of the pathophysiology of CF and clarified genotype-phenotype relationships, it was not until 2012 that an agent targeted towards correcting the defective protein became a reality [6]. Until then, the available therapies could only improve symptoms and slow down the progression of the disease. Nevertheless, such therapies transformed CF from a fatal disease of children to a more treatable, albeit still fatal, chronic disease of adults [7].The most recent and swiftly evolving therapies in CF therapeutic pipeline are the CFTR modulator targeting the abnormal protein. The CFTR protein is a cAMP protein kinase chloride ion channel that regulates chloride and bicarbonate transport across the epithelial cell surface and, in turn, inhibits the absorption of sodium absorption. CFTR protein is encoded by the CF gene located on chromosome 7 (7q31.2) and is found in epithelial cells of the airway, intestine, pancreas, and sweat gland. In CF, the CFTR protein defect is dependent on the Class of CFTR mutations, and total CFTR activity is determined by the CFTR quantity and function [8]. There are six classes of CFTR mutations (Table 1)The full explanation of CF airway pathology is beyond this review. Briefly, normal cilia require a hydrated airway surface liquid layer to function appropriately in mucociliary clearance.When chloride ion transport is impaired or absent based on the type of CFTR mutation, sodium is hyper-absorbed along with water, resulting in a poorly hydrated airway surface liquid layer. This leads to a continual cycle of thick mucus, airway obstruction and inflammation, tissue injury and resultant bronchiectasis.Once bronchiectatic airways develop, airway clearance is not optimal. This environment promotes the acquisition of bacteria that become pathogenic in CF lungs [9,10]. This article summarizes the available treatments for CF categorized by the mechanism of action.We begin by explaining traditional CF therapies and go on to describe CFTR modulator therapy in more detail. Airway Clearance TherapiesAirway clearance remains a mainstay of CF therapy and is encouraged from birth to adulthood [10]. However, since many clinical tri...

Lung Transplantation in a New Era in the Field of Cystic Fibrosis

“…Mutation Classes I through III are more commonly associated with more severe lung dysfunction and pancreatic insufficiency (PI). Class IV and V mutations are related to defects in channel conductance and stability, respectively; these result in proteins that have residual function and are usually associated with milder disease severity compared to Classes I, II, and III [8]. Absent or dysfunctional CFTR protein in the airways results in the accumulation of thickened secretions that are unable to be cleared by cilia, which leads to chronic airway infections, inflammation, and bronchiectasis.…”