Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis

Romani, Luigina; Oikonomou, Vasileios; Moretti, Silvia; Iannitti, Rossana Giulietta; D’Adamo, Maria Cristina; Villella, Valeria Rachela; Pariano, Marilena; Sforna, Luigi; Borghi, Monica; Bellet, Marina Maria; Fallarino, Francesca; Pallotta, Maria Teresa; Servillo, Giuseppe; Ferrari, Eleonora; Puccetti, Paolo; Kroemer, Guido; Pessia, Mauro; Maiuri, Luigi; Goldstein, Allan L.; Garaci, Enrico

doi:10.1038/nm.4305

Cited by 88 publications

(97 citation statements)

References 67 publications

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“…It has been reported that 24-hour treatment with Tα-1 causes an increase in the expression of mature (fully glycosylated) CFTR, paralleled by an increase in CFTR function and potentiation of CaCC activity (as evidenced by microfluorimetric and electrophysiological assays including short-circuit current measurements and patch-clamp analysis) (26). We tested Tα-1 on well-differentiated primary cultures of human bronchial epithelial cells from 3 different F508del homozygous subjects by using electrophysiological and biochemical techniques (Figure 1).…”

Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

“…We wondered whether the lack of CFTR rescue observed in our laboratories using biochemical techniques could be due to the different antibody used as compared with Romani and collaborators (26), using CF3 antibody originally developed by Pier and collaborators (48).…”

Section: Tα-1 Does Not Alter F508del-cftr or Cacc Currents As Evidencmentioning

confidence: 99%

“…The CF3 antibody was used under the same conditions used by Romani and collaborators (26). Surprisingly and unexpectedly, the CF3 antibody (C) Representative whole-cell membrane currents from patch-clamp experiments on CFBE41o-cells treated for 24 hours with DMSO alone (0.1%), scrambled peptide (100 ng/ml + 0.1% DMSO), or Tα-1 (100 ng/ml + 0.1% DMSO).…”

Section: Tα-1 Does Not Alter F508del-cftr or Cacc Currents As Evidencmentioning

confidence: 99%

“…Very recently, it has been reported that thymosin α-1 (Tα-1), a naturally occurring polypeptide acting as an immunomodulator (25), represents a potential single-molecule-based therapy for cystic fibrosis (26). Indeed, Romani and colleagues showed that Tα-1 reduces inflammation and increases CFTR maturation, stability, and activity, thus completely reverting pathological phenotypes due to F508del-CFTR mutants, both in vitro, in the CFBE41o-cell line and in human primary bronchial epithelia, and in vivo, in a CF mouse model (26).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, Romani and colleagues showed that Tα-1 reduces inflammation and increases CFTR maturation, stability, and activity, thus completely reverting pathological phenotypes due to F508del-CFTR mutants, both in vitro, in the CFBE41o-cell line and in human primary bronchial epithelia, and in vivo, in a CF mouse model (26). Such a drug would be of primary importance for CF patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

Section: Tα-1 Does Not Alter F508del-cftr or Cacc Currents As Evidencmentioning

confidence: 99%

Section: Tα-1 Does Not Alter F508del-cftr or Cacc Currents As Evidencmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Physiology of Electrolyte Transport in the Gut: Implications for Disease

Rao

2019

Comprehensive Physiology

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We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

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Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

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Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis

Cited by 88 publications

References 67 publications

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

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

Physiology of Electrolyte Transport in the Gut: Implications for Disease

Inflammation in cystic fibrosis: An update

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