Eluforsen, an investigational therapy for the treatment of cystic fibrosis (CF), improves the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in cellular and mice models of CF that carry the most common mutation associated with the disorder, a study says.
The findings of the study, “Evaluation of eluforsen, a novel RNA oligonucleotide for restoration of CFTR function in in vitro and murine models of p.Phe508del cystic fibrosis,” were published recently in the journal PLOS ONE.
CF is a genetic disorder caused by mutations in the CFTR gene, which provides instructions to make the CFTR protein. This protein works as a channel that transports molecules, such as chloride and water, in and out of cells.
The F508 deletion is the most common mutation associated with the disease, in which the deletion of three nucleotides (the building blocks of DNA) in the gene sequence lead to the elimination of an amino acid called phenylalanine from the CFTR protein sequence at position 508 (p.Phe508del). This leads to incorrect protein folding and premature protein degradation, which prevent CFTR from reaching the cell membrane and performing its function.
Eluforsen (formerly known as QR-010) is an experimental therapy developed by ProQR Therapeutics; it is designed to correct the F508 deletion by modifying the RNA molecule that cells use as a final template for producing the CFTR protein.
In the study, researchers from ProQR, in collaboration with investigators from the Université Catholique de Louvain, Belgium, set out to demonstrate how cells uptake (absorb) eluforsen, and how effective the therapy is in restoring the activity of CFTR in cells and mice models of CF carrying the F508 deletion.
Experiments performed in pancreatic cancer cells isolated from a patient with CF demonstrated that eluforsen treatment increased the transport of chloride from the inside to the outside of the cells. In addition, experiments in primary cells from the lungs of CF patients showed that treatment with eluforsen increased the cells’ short-circuit current, “both indicating restoration of CFTR function [in vitro],” the researchers wrote.
Experiments in mice models demonstrated that eluforsen was easily uptaken by cells from the lungs after being administered through their mouth/windpipe (to mimic inhalation in patients), leading to a systemic exposure to therapy.
In female mice carrying the F508 deletion, treatment with eluforsen significantly increased the release of saliva in response to beta-adrenergic stimulation (a chemical cascade that induces relaxation of the airways’ muscles, making it easier to breathe), which normally is used as a readout of CFTR function, much like the sweat test is used in CF patients.
In addition, the team found that when administered through the nose, eluforsen improved the nasal potential difference (NPD), and subsequently CFTR conductance, in two different animal models of CF. (Of note, NPD refers to changes in the electrical charge of cells forming the nasal epithelium, which is possible only due to CFTR.)
Overall, the “findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF, and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by NPD,” researchers wrote.
According to the team, “these encouraging preclinical data served as the foundation for two human clinical trials of eluforsen in patients with p.Phe508del-CFTR-mediated CF (NCT02564354 and NCT02532764).”