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

Armirotti, Andrea; Tomati, Valeria; Matthes, Elizabeth; Veit, Guido; Cholon, Deborah M.; Phuan, Puay‐Wah; Braccia, Clarissa; Guidone, Daniela; Gentzsch, Martina; Lukacs, Gergely L.; Galietta, Luis J V; Hanrahan, John W.; Pedemonte, Nicoletta

doi:10.1038/s41598-019-46639-1

Cited by 8 publications

(10 citation statements)

References 66 publications

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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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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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“…In that context, cysteamine, approved for the treatment of cystinosis [ 207 ], was tested in CF mice, followed by a small open-label clinical trial in PwCF, where it was shown to reduce sweat chloride levels in F508del carrying PwCF, but not in a cohort which contained PwCF carrying two non-F508del mutations not responsive to current CFTR modulators [ 208 , 209 ]. More recently, however, functional rescue by cysteamine and thymosin α1—the rescue by the latter also reported to occur through promoting autophagy [ 210 ]—could not be confirmed by several other labs [ 211 , 212 , 213 ], dampening the enthusiasm to stimulate autophagy as a way of reversing the CF phenotype.…”

Section: Cftr Causal Therapiesmentioning

confidence: 99%

One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

Ensinck

Carlon

2022

Cells

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Cystic fibrosis (CF) is the most common monogenic disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Over the last 30 years, tremendous progress has been made in understanding the molecular basis of CF and the development of treatments that target the underlying defects in CF. Currently, a highly effective CFTR modulator treatment (Kalydeco™/Trikafta™) is available for 90% of people with CF. In this review, we will give an extensive overview of past and ongoing efforts in the development of therapies targeting the molecular defects in CF. We will discuss strategies targeting the CFTR protein (i.e., CFTR modulators such as correctors and potentiators), its cellular environment (i.e., proteostasis modulation, stabilization at the plasma membrane), the CFTR mRNA (i.e., amplifiers, nonsense mediated mRNA decay suppressors, translational readthrough inducing drugs) or the CFTR gene (gene therapies). Finally, we will focus on how these efforts can be applied to the 15% of people with CF for whom no causal therapy is available yet.

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“…Interestingly, the study also showed that Tα1 was capable of increasing CFTR maturation, stability, and activity [54,55]. Nevertheless, this latter effect was not confirmed by subsequent studies [56,57]. More recently, the group of Romani and colleagues suggested that Tα1 can also have beneficial effects in CF extrapulmonary pathology.…”

Section: Thymosin Alpha-1mentioning

confidence: 98%

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

Ghigo

Prono

Riccardi

et al. 2021

IJMS

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Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

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

Cited by 8 publications

References 66 publications

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

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

One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

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