Strategies for the etiological therapy of cystic fibrosis

Abstract

Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies.

Stem cell-based Lung-on-Chips: The best of both worlds?

“…5C). CFTR modulators demonstrated that direct repair of the malfunctioning protein can partly restore normal lung function [188]. However, this treatment requires continuous pharmacological intervention.…”

Etiological involvement of CFTR in apparently unrelated human diseases

“…Loss-of-function mutations of CFTR cause the most frequent human monogenetic lethal disease, cystic fibrosis (CF). 1 The pathogenesis of CF involves two complementary phenomena. On one hand, failure to transport chloride anions into the extracellular space increases the viscosity and thickness of mucus, hence compromising its elimination from the respiratory tract (which facilitates chronic inflammation coupled to recurrent pulmonary infections) and the pancreatic ducts (which drives failure of the exocrine pancreas and consequent nutrient malabsorption).…”

“…On one hand, failure to transport chloride anions into the extracellular space increases the viscosity and thickness of mucus, hence compromising its elimination from the respiratory tract (which facilitates chronic inflammation coupled to recurrent pulmonary infections) and the pancreatic ducts (which drives failure of the exocrine pancreas and consequent nutrient malabsorption). 1 On the other hand, imbalances in intracellular anion fluxes (perhaps combined with deficient CFTR scaffold functions) favor a progressive and irreversible imbalance in proteostasis due to activation of transglutaminase 2 (TGM2) and reduced beclin 1 (BECN1) expression, culminating with inhibition of autophagy. [1][2][3][4] These three phenomena (deficient CFTR function, TGM2 activation, and autophagy impairment) amplify each other in a feed-forward circuitry, locking affected cells in a close-to-irrevocable proinflammatory state that contributes to disease pathogenesis.…”

“…1 On the other hand, imbalances in intracellular anion fluxes (perhaps combined with deficient CFTR scaffold functions) favor a progressive and irreversible imbalance in proteostasis due to activation of transglutaminase 2 (TGM2) and reduced beclin 1 (BECN1) expression, culminating with inhibition of autophagy. [1][2][3][4] These three phenomena (deficient CFTR function, TGM2 activation, and autophagy impairment) amplify each other in a feed-forward circuitry, locking affected cells in a close-to-irrevocable proinflammatory state that contributes to disease pathogenesis. [5][6][7] Inhibiting each of the cornerstones of this triad can improve CF pathogenesis, as demonstrated by clinical trials using CFTR-stimulatory agents (so-called "CFTR potentiators"), TGM2 inhibitors, and autophagy enhancers.…”

Relação entre genótipo e insuficiência pancreática em crianças e adolescentes com fibrose cística de um centro de referência no Brasil

“…A FC possui um caráter multissistêmico, apresentando um quadro clínico variável e com grande diversidade na gravidade e na evolução clínica (ARIAS LLORENTE; BOUSOÑO GARCÍA; DÍAZ MARTÍN, 2008;WELSH et al, 2001). O fenótipo da FC inclui a elevação de eletrólitos no suor e pode compreender insuficiência pancreática (IP), doenças gastrointestinais e hepatobiliares, além de infertilidade masculina (MAIURI; RAIA; KROEMER, 2017, ROSA et al, 2018.…”