thymalfasin and Cystic-Fibrosis

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.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Cannabinoids; COVID-19; COVID-19 Drug Treatment; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Eicosanoids; Humans; Inflammation; Protein Kinase Inhibitors; Roscovitine; Signal Transduction; Thymalfasin

Cystic fibrosis (CF) is an inherited recessive autosomal disorder that affects the lungs, the digestive system, and secretory glands. It is a lethal condition caused by a mutation in the gene cystic-fibrosis-transmembrane-conductance- regulator (CFTR), which leads to defects in ion channels and results in obstruction of mucus in airway channels. Unbalanced ion exchange causes impaired water transport and accumulation of viscous mucus in the air way leads to bacterial colonization, for example, with Staphylococcus aureus. The most common mutation is the deletion of nucleotides in epithelial membrane; hence, it is a multiple-organ-defective disease that mostly effects the lungs. Researchers are working on gene therapy that aims to introduce a normal CFTR gene copy into the epithelial cells of lungs. Several approaches have been designed to improve transepithelial ion transport in CF patients. Normal CFTR gene delivery has been performed using viral and nonviral vectors, but these approaches are not more efficient against the cell barriers. Enzymes may be used that inhibit the sphingolipid to provide proper microenvironment for the CFTR gene product. Thymosin alpha-1 has also been reported as a potential corrector in treatment of CF.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy; Epithelium; Genetic Therapy; Glucosylceramidase; Humans; Ion Transport; Liposomes; Membrane Proteins; Mutation; Staphylococcal Infections; Staphylococcus aureus; Thymalfasin

Cystic fibrosis (CF) is a multisystem illness caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene and protein. CFTR is an ion channel regulating transport of chloride, bicarbonate, and water, and influencing sodium resorption. It is inherited as an autosomal recessive disorder, and with about 70,000 CF patients worldwide, it is the most common life shortening disease among persons of European descent. CFTR disease-causing mutations have been organized into six classes. :. Recently, small molecule targeted therapy for specific classes of CFTR abnormalities have included CFTR correctors that decrease protein degradation and CFTR potentiators that increase channel open probability enhancing chloride transport.. Although there are many novel medications in preclinical and clinical testing, there is need for safe and effective CFTR modulating drugs and immunomodulatory medications to decrease the abundant neutrophilic inflammation response in the airway without unwanted adverse effects. Thymosin alpha 1 treatment of airway cells isolated from phe508del CF patients and from CF knockout mice, decreased inflammation, increased CFTR maturation, and facilitated translocation of CFTR protein to the plasma membrane increasing channel activity. If similar results are seen in humans with CF, thymosin alpha 1 has the unique potential to be a single molecule therapy for treating CF airway disease.

Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Discovery; Health Services Needs and Demand; Humans; Inflammation; Mice; Mice, Knockout; Mutation; Thymalfasin

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding for the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Long considered a lung disease for the devastating impact on the respiratory function, the recent diagnostic and therapeutic advances have shed the light on the extra-pulmonary manifestations of CF, including gastrointestinal, hepatobiliary and pancreatic symptoms. We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that concur in ameliorating the lung inflammatory pathology. In the present study, by resorting to murine models of gut inflammation with clinical relevance for CF patients, we demonstrate that Tα1 can also have beneficial effects in extrapulmonary pathology. Specifically, Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice as well as in mice with the metabolic syndrome, a disorder that may arise in CF patients with high caloric intake despite pancreatic sufficiency. The protective effects of Tα1 also extended to pancreas and liver, further emphasizing the beneficial effects of Tα1 in extra-pulmonary complications of CF. By performing wide-ranging multi-organ anti-inflammatory effects, Tα1 could potentially integrate current therapeutic approaches to tackle the complex symptomatology of CF disease.

Topics: Animals; Candida albicans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Homeostasis; Humans; Immunologic Factors; Kynurenine; Liver; Lung; Mice; Mutation; Obesity; Pancreas; Signal Transduction; Thymalfasin

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.

Topics: Animals; Autophagy; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; MCF-7 Cells; Primary Cell Culture; Protein Transport; Sequence Deletion; Thymalfasin

In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. Considering the numerous effects of the F508del mutation on the assembly and processing of CFTR protein, combination therapy with several pharmacological correctors is likely to be required to treat CF patients. Recently, it has been reported that thymosin α-1 (Tα-1) has multiple beneficial effects that could lead to a single-molecule-based therapy for CF patients with F508del. Such effects include suppression of inflammation, improvement in F508del-CFTR maturation and gating, and stimulation of chloride secretion through the calcium-activated chloride channel (CaCC). Given the importance of such a drug, we aimed to characterize the underlying molecular mechanisms of action of Tα-1. In-depth analysis of Tα-1 effects was performed using well-established microfluorimetric, biochemical, and electrophysiological techniques on epithelial cell lines and primary bronchial epithelial cells from CF patients. The studies, which were conducted in 2 independent laboratories with identical outcome, demonstrated that Tα-1 is devoid of activity on mutant CFTR as well as on CaCC. Although Tα-1 may still be useful as an antiinflammatory agent, its ability to target defective anion transport in CF remains to be further investigated.

Topics: Anions; Bronchi; Cell Line, Tumor; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Primary Cell Culture; Protein Folding; Respiratory Mucosa; Thymalfasin

Topics: Cell Line; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Thymalfasin

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

Topics: Adjuvants, Immunologic; Animals; Autophagy; Blotting, Western; Cell Line; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Disease Models, Animal; Epithelial Cells; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunoprecipitation; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Mice; Mice, Inbred CFTR; Patch-Clamp Techniques; Protein Stability; RAW 264.7 Cells; Respiratory Mucosa; Thymalfasin; Thymosin; Ubiquitin Thiolesterase; Ubiquitination

Topics: Adjuvants, Immunologic; Cystic Fibrosis; Humans; Thymalfasin; Thymosin