Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Tomati, Valeria; Caci, Emanuela; Ferrera, Loretta; Pesce, Emanuela; Sondo, Elvira; Cholon, Deborah M.; Quinney, Nancy L.; Boyles, Susan E.; Armirotti, Andrea; Ravazzolo, Roberto; Galietta, Luis J V; Gentzsch, Martina; Pedemonte, Nicoletta

doi:10.1172/jci.insight.98699

Cited by 24 publications

(21 citation statements)

References 56 publications

(86 reference statements)

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“…For control, 0.1% of the vehicle DMSO was applied to the apical surface of the CF and non-CF epithelia. We have previously demonstrated that this concentration does not affect the vitality and function of differentiated epithelia [26]. Indeed, we have not observed differences in any in any of the analysed parameters between non-DMSO (data not shown) and DMSO treatment.…”

Section: Impact Of the Anionophores On The Asl Propertiessupporting

confidence: 45%

Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

Gianotti

Capurro

Delpiano

et al. 2020

IJMS

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Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy.

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Section: Impact Of the Anionophores On The Asl Propertiessupporting

confidence: 45%

Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

Gianotti

Capurro

Delpiano

et al. 2020

IJMS

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“…Both cysteamine and thymosin a-1 were also claimed to restore functional expression of F508del-CFTR (Tosco et al, 2016;Romani et al, 2017). Nevertheless, several independent CF research groups failed to demonstrate rescue of F508del-CFTR PM expression and function by either cysteamine or thymosin a-1 (Tomati et al, 2018b;Armirotti et al, 2019;Awatade et al, 2019). Although the immunomodulatory effect of these molecules in CF remains to be further exploited, they did not demonstrate F508del-CFTR correction.…”

Section: Identifying Feasible Solutions For a Cf Healthcare Cost Sustmentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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“…Our previous studies conducted in three independent laboratories failed to detect Tα-1 activity as modulator of mutant CFTR maturation and function on primary bronchial epithelia from F508del homozygous patients by using biochemical and electrophysiological techniques 39,40 . These results were obtained by testing Tα-1 from two different commercial sources (CRIBI and Abcam) and using different protocols for peptide solubilization (Tα-1 powders were dissolved in either distilled water, DMSO or 0.1% acetic acid).…”

Section: Resultsmentioning

confidence: 97%

“…The enthusiasm for these findings however waned when three independent laboratories were unable to reproduce the results 39,40 . Romani and colleagues replied to these studies by calling into question the acetylation status and handling of the Tα-1 peptide, in particular the vehicle used 41 .…”

Section: Introductionmentioning

confidence: 99%

Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity

Armirotti

Tomati

Matthes

et al. 2019

Sci Rep

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Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.

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Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Cited by 24 publications

References 56 publications

Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity

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