cystic fibrosis – Drug Discovery Opinion

New Approach to Cystic Fibrosis

Cystic fibrosis (CF) results from a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) that results in impaired transport of chloride and bicarbonate ions. Patients with CF have thickened mucus, accompanied by inflammation, which affects the lungs and organs of the intestinal tract. Although the disease has received much scientific attention, current treatments only manage the symptoms and affected individuals continue to suffer from reduced life expectancy.

A new study from researchers at University of California, San Diego School of Medicine, has now identified defects in signalling mediated by peroxisome proliferator-activated receptor-γ (PPAR-γ) that contribute to disease symptoms. Examining colonic epithelial cells and whole lung tissue from CFTR-deficient mice, the team found reduced expression of genes that are normally activated by PPAR-γ. Lipidomic analysis of the colonic epithelial cells suggested that the defect resulted in part from reduced amounts of the endogenous PPAR-γ ligand, 15-keto-prostaglandin E₂ (15-keto-PGE₂). The researchers were able to partially restore gene expression by treating the mice with rosiglitazone, a PPAR-γ agonist used in the treatment of diabetes, reducing the severity of disease.

PPar pathway — PPAR-α and -γ Signalling; Image:Mark Somoza

Rosiglitazone had no effect on chloride secretion in the colon, but increased expression of carbonic anhydrases 2 and 4 (Car2 and Car4) resulting in increased bicarbonate secretion and reduced mucus retention.

The study, published in Nature Medicine, suggests that levels of 15-keto-PGE₂ could provide a marker for patients who might benefit from treatment with a PPAR-γ agonist.

A Rebalancing Approach to Cystic Fibrosis

Cystic fibrosis is an inherited disease that affects about 70,000 children and adults worldwide. The condition is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). Defects in the protein product – which transports chloride ions – lead to unusually thick, sticky mucus that clogs the lungs and also blocks the ducts of the pancreas, preventing digestive enzymes from reaching the intestine. The most common mutation, which causes a severe form of the disease, is a deletion of a phenylalanine residue at position 508 of the protein (DF508 CFTR) which results in the absence of CFTR protein at the cell surface. Current treatments for cystic fibrosis focus primarily on managing the symptoms and drugs that are able to restore function of DF508 CFTR protein at the cell surface, which would benefit the majority of cystic fibrosis patients, are not available.

A new study by Scripps scientists working in collaboration with investigators from the US and Canada has now shown, however, that the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), can restore about 28 percent of normal ion channel function to cultures of lung epithelial cells from patients with the DF508 CFTR mutation. The team speculated that mutant CFTR proteins – which could still provide some useful function – were being degraded by the endoplasmic reticulum and reasoned that modifying HDAC function might rebalance proteostasis networks in the cell to favour functional restoration. When the cells were treated with SAHA, DF508 CFTR was expressed at the cell surface at comparable levels to wild-type protein. Inhibition of HDAC7 appeared to be largely responsible for this effect although little is known about the physiological role of HDAC7. Since it is known that cystic fibrosis patients with 15-30% of normal CFTR function have milder disease, the level of functional restoration provided HDAC7 inhibition has the potential to provide significant benefit.

SAHA (vorinostat) is currently approved for the treatment of cutaneous T-cell lymphoma (CTCL), but the researchers caution that much more work will be needed before this approach can lead to new therapies for cystic fibrosis.

The study, published in Nature Chemical Biology, takes a new approach to drug discovery by targeting cellular proteostasis and could have application in numerous chronic diseases that are characterised by protein misfolding.

Antioxidant Role for Thiocyanate: Implications for Cystic Fibrosis Treatment

Vegetables such as cauliflower and broccoli are a natural source of dietary thiocyanate

Image: Flickr - Clayirving

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder affecting the secretory glands, resulting from mutations in the CF transmembrane conductance regulator (CFTR) gene. The disease predominantly involves the respiratory and digestive systems, with lung injuries and infections responsible for approximately 90% of the morbidity and mortality of CF patients.

CFTR encodes a chloride conducting channel and the CF-causing mutations result in reduced numbers and/or defective ion channels. Although the link between mutated CFTR and CF has been known for 20 years, the fundamental question of how this results in disease has remained elusive. Contrary to expectations, the levels of Cl^– in the airways of CF patients are not very different to those found in unaffected individuals.

It is known, however, that CFTR channels are able to conduct other ions, including thiocyanate (SCN^–), and new research from scientists at the Howard Hughes Medical Institute and University of Pennsylvania School of Medicine now suggests that defective SCN^– transport may play a role. Thiocyanate has antioxidant properties, providing protection from reactive oxygen species (ROS) that are formed in response to infection. Transport of thiocyanate into the airway lumen results in higher concentrations in airway secretions than in plasma and is dependent on functional CFTR. In this study, the researchers showed that lactoperoxidase in the airways catalyses the conversion of SCN^– to tissue-innocuous hypothiocyanite (OSCN^–), consuming potentially damaging hydrogen peroxide in the process. Further, SCN^– depletes harmful hypochlorite (OCl^–) through competition with chloride ion for myeloperoxidase and by direct reduction.

The authors of the study, published in PNAS, suggest that as well as a potential role in the pathogenesis of CF, insufficient levels of SCN^– may provide inadequate protection from hypochlorite, exacerbating inflammatory diseases.

New Results for PTC124 in Cystic Fibrosis

Cystic fibrosis (CF) is a hereditary disease characterised by the production of thick sticky mucus which results in frequent lung infections. CF is caused by any one of a number of mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) which encodes a protein that transports chloride ions across cell membranes. In about 10% of patients worldwide, and more than 50% of patients in Israel, CF is caused by nonsense mutations in the messenger RNA for CFTR. Premature stop codons prevent production of functional full-length protein: patients with nonsense-mutation CF produce very little functional CFTR and often have a severe form of CF.

New Phase II results published in The Lancet show that an orally bioavailable small molecule demonstrates activity in nonsense-mutation CF. PTC124 was designed to induce ribosomes to selectively read through premature stop codons to produce functional CFTR. The data show that treatment with PTC124 results in statistically significant improvements in the chloride channel function of patients.

PTC124
Nonsense mutations account for a significant number of cases of most inherited diseases and PTC124 may have the potential to treat diseases other than CF.