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.