Compound Shows Early Potential in Treating CF Due to F508del Mutation

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A small compound called c407 restored the function of CFTR — the defective protein in cystic fibrosis (CF) — and its associated chloride flow in mice carrying F508del, the most common CF-causing mutation, a study shows.

These benefits were associated with a stabilization of CFTR’s folding and its increased transport to the cell surface, where it exerts its function.

Continuous under-the-skin treatment with c407 for nearly one month was generally well-tolerated, further supporting additional research on the compound’s potential as a F508del-CFTR corrector, the researchers noted.

The study, “Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice,” was published in the journal Scientific Reports.

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CF is caused by a faulty CFTR, a channel protein that normally controls the flow of water and chloride ions (salt) through cells, due to mutations in the CFTR gene. CFTR deficiency leads to the accumulation of thick and sticky mucus in the airways, “favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure,” the researchers wrote.

F508del, a common mutation, leads to a deletion of an amino acid called phenylalanine from the CFTR protein sequence at position 508 (p.Phe508). Amino acids are protein’s building blocks.

This deletion results in the CFTR protein’s incorrect folding and premature degradation, which prevent it from reaching the cell surface and working as it should. Even if some of the defective protein reaches its destination, it is unable to function and allow the passage of chloride ions.

In a previous study, researchers in Europe identified a small compound called c407 as a potential CFTR modulator for deficits caused by the F508del mutation. They found that c407 promoted F508del-CFTR’s partial restoration in lab-grown human cells and in mice given the compound directly into the nose.

Further research showed that c407 occupies the position of the missing p.Phe508 amino acid, stabilizing CFTR protein folding through a different mechanism of action than lumacaftor, a CFTR corrector used in the approved therapy Orkambi.

The compound is also thought to promote CFTR’s transport to the cell surface by suppressing its interaction with a protein called keratin 8.

Notably, combining c407 with Orkambi resulted in increased efficacy at restoring CFTR function in lab-grown human cells carrying the F508del mutation, suggesting that c407 may be “a potential cotherapy of other CFTR correctors,” the researchers wrote.

To better understand c407’s potential, the team now evaluated the effects of short- and long-term systemic treatment with c407 in mice carrying the F508del mutation.

Short-term treatment involved injections of a higher dose into the abdominal cavity three times a day for three days, while long-term use involved continuous, under-the-skin administration of a lower dose for 28 days through a surgically implanted device.

CFTR function was assessed through the nasal potential difference test, which measures changes in electrical charge derived from the passage of chloride ions through the surface of cells lining the nose.

Results showed that both regimens significantly increased CFTR-dependent chloride ion flow in the animals, reaching 93% of normal reference levels for the abdominal route and 47% for the under-the-skin route. Further analysis confirmed that c4070’s effects were dose-dependent.

Observed improvements in CFTR function with c407 were also found to be associated with an increased localization of F508del-CFTR at the surface of nasal cells.

Both c407 treatment approaches were generally well tolerated, with no unusual findings in terms of weight gain, death rate, organ damage at autopsy, or evidence of changes in well-being. Studies on the absorption, distribution, metabolism, excretion, and toxicity of c407 also supported a favorable tolerance profile.

The compound did not have a major effect on other relevant molecules, except for the MAO-B enzyme, whose activity was suppressed by 50%. MAO-B is involved in the breakdown of chemical messengers in the brain.

“This may be a collateral effect and should only prove toxic if the [compound reaches the brain], which must be evaluated,” the researchers wrote.

These findings “provide the first [animal] preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis,” the team wrote.

While the data support c407 as a potential therapy for CF associated with the F508del mutation, the compound’s independent ability to promote CFTR transport to the cell membrane “might be useful in other misfolding mutations than F508Del,” they added.

Researchers also noted that c407’s effectiveness appeared to be more mild in lab-grown airway cells from CF patients used in their previous studies. But its combination with other CFTR correctors may strengthen its effects.

Future research is needed to confirm this, as well as the safety and efficacy of c407 given orally to mice in CF models. Should this preferred route prove ineffective, “inhaled topical administration might thus be considered,” the team concluded.