Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Abstract

Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.

Nutritional Care in Children with Cystic Fibrosis

“…CFTR modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. They are mainly represented by small molecules that can be divided into the following categories [ 172 , 173 ]:…”

“…Ivacaftor belongs to the potentiator category of CFTR modulators and it was the first one approved in 2012 by FDA and EMA for patients carrying the G551D gating mutation and aged at least six years old [ 173 , 174 ]. Since then, its use has been expanded to many other mutations and to younger ages: to date, 97 CFTR gene mutations are responsive to Kalydeco ® , and the age from which it is possible to start treatment has been reduced to four months [ 173 , 174 ].…”

“…Regarding the other CFTR modulators currently in use, it must first be said that studies on their nutritional effects are not as numerous as the ones made for ivacaftor, mainly for their most recent approval. Lumacaftor is a first-generation corrector, but it also operates as a stabilizer [ 173 ]. It has been approved in combination with the potentiator ivacaftor [ 180 ] for F508del-homozygous patients aged over 12 years.…”

“…Finally, both tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor will need more studies to better understand the impact they have on the nutritional sphere, given the few studies specifically projected for this field [ 173 ]. However, given the accumulating evidence for the previously approved CFTR modulators with a pretty similar mechanism of action, it is likely that the multiple causes underlying the improvement of the nutritional status can be shared between this category of drugs.…”

Immune Response in Cystic Fibrosis: Interplay between the Host and Microbes

“…Related to this review, Meoli et al [10] review the literature on the impact of CFTRtargeted molecules on phagocytes, including not only macrophages but neutrophils. The effect of different CFTR-approved therapies is presented.…”