Difficult CF Mutation May Be Treatable by Targeting Its CFTR Defect Indirectly via Proteins, Study Suggests

Difficult CF Mutation May Be Treatable by Targeting Its CFTR Defect Indirectly via Proteins, Study Suggests

A scientific paper published by Spanish researchers discusses a strategy for treating the difficult-to-target F508del-CFTR mutation, a cause of cystic fibrosis (CF). The report, Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis, appeared on March 14 in the journal Molecular and Cellular Pediatrics.

CF is one of the most commonly occurring chronic diseases of the lungs in children and young adults. Breathing is often difficult for CF patients, due to a sticky mucus that builds up and often leads to serious bacterial lung infections. Mutations in the CFTR gene are the major cause of this mucus buildup.

Scientists have identified over 2,000 mutations in the CFTR gene that are associated with the disease, which normally presents in patients at birth. CFTR, which stands for cystic fibrosis transmembrane conductance regulator, helps shuttle chloride ions in and out of cells, balancing salt and water in the cells that line the lungs.

Most treatments focus on repairing the CFTR itself. The F508del-CFTR defect is one cause of CF, and this particular defect has less responsiveness to CF experimental and clinical treatments, such as the medication Ivacaftor. New approaches appear to be required for these patients.

Researchers reviewed strategies targeting proteostasis, which involves biological pathways responsible for the synthesis, use, and break down of proteins. These approaches would involve drug candidates targeting molecules that interact with the mutant CFTR protein, rather than trying to repair CFTR itself. According to the authors, “Manipulation of proteostasis network offers new perspectives for the design of candidate drugs aimed at repairing the primary CFTR defect, well beyond the idea that such molecules must directly interact with mutant CFTR protein.”

The team recommend using both animal models and cultured cells to identify proteins affected by CFTR mutations. But to identify these targets, the consequences of the CFTR mutation first need to be fully understood. In their report, the authors noted “finding appropriate proteostasis regulators implies a profound understanding of the pathogenic mechanisms operating within each peculiar cellular context.”

A Phase 2 pilot trial examining the proteostasis regulators cysteamine and EGCG in patients with the F508del-CFTR mutation reported a reduction in CF symptoms using this approach. In addition, sputum CF markers (cytokines) declined and sweat chloride concentrations decreased, both indicators of an effective CF treatment.

The authors speculated that proteostasis regulators could aid in the treatment of CF, and potentially in other diseases characterized by abnormal proteins, such as certain neurological conditions.

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