Drug improves cystic fibrosis pulmonary inflammation and protein function [PreClinical]

1. Thymosin α1 (Tα1), an immunomodulatory drug currently in use, decreased lung inflammation in a mouse model of cystic fibrosis (CF).

2. In mice, administration of Tα1 improved the localization and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

Evidence Rating Level: 1 (Excellent)

Study Rundown: CF is a disorder caused by mutations in the gene that encodes the CFTR protein, leading to chronic pulmonary infections as well as other complications. Therapies for this condition involve improving the function of the mutated CFTR and using immunomodulatory therapies to suppress the hyperinflammatory response of these patients. This study investigated the potential for Tα1 (Zadaxin), an immunomodulatory drug currently used to treat viral infections and other conditions, to address both of these aspects of treating CF.

In a mouse model of CF, the administration of Tα1 led to a decrease in pro-inflammatory markers and an increase in anti-inflammatory markers. In CF cells and mice, treatment with Tα1 increased CFTR expression at the plasma membrane through reducing endosomal targeting. This increase in cell surface expression was accompanied by an increase in activity of the protein, demonstrating potential pulmonary function improvement following treatment with Tα1.

This study elucidated a promising candidate therapy for CF. By simultaneously addressing the need to improve CFTR activity and reduce inflammation in CF, this drug demonstrated potential as a single-molecule CF therapy. In addition, since this drug is already currently on the market and is known to be safe, future clinical trials can focus on testing its efficacy in patients with CF.

Click here to read the study Nature Medicine

Relevant Reading: New and emerging targeted therapies for cystic fibrosis

In-Depth [animal study]: An airway epithelial cell line expressing p.Phe508del-CFTR, the most common mutation seen in patients with CF, was treated with Tα1. There was an increase in expression of IDO1, a protein involved in immune tolerance and known to be defective in CF patients. Next, Tα1 was administered to mice with the p.Phe508del-CFTR mutation that were infected with Aspergillus fumigatus to establish chronic lung disease. Treatment led to a decrease in lung pathology, fungal growth (p<0.0001), and neutrophil infiltration (p<0.0001). In addition, levels of pro-inflammatory cytokines such as TNF-α and IL-17A were decreased while levels of anti-inflammatory cytokines such as IL-10 were increased (p<0.01).

Next, the effect of Tα1 on CFTR function was evaluated. After treating p.Phe508del-CFTR airway epithelial cells with Tα1, western blotting demonstrated an increase in the plasma membrane localization of CFTR (p<0.001). CTFR was found to colocalize with Rab9, a marker of recycling endosomes, indicating that Tα1 improved CTFR function by decreasing breakdown and inducing proper folding. Tα1 also increased the half-life of the mutant CFTR through the reduction of ubiquitination, as demonstrated by immunoprecipitation and western blotting (p<0.05).

In p.Phe508del-CFTR mice treated for 6 days with Tα1, histology showed increased plasma membrane localization of CFTR. The function of the mutated CFTR was assessed through measuring chloride ion conductance using patch-clamp experiments following forskolin and genistein stimulation. Tα1 restored channel activity and gating in the lung epithelial cells of these mice, leading to a two-fold increase in open probability.

Image: PD

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