Restoring DF508-CFTR trafficking and activity with epigenetic modifiers

Cystic fibrosis (CF) is an early onset disease characterized by a defect in the apical chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR). The most common disease causing mutation is a 3 basepair deletion resulting in loss of Phe 508 (ΔF508), which leads to misfolding and efficient endoplasmic reticulum associated degradation (ERAD) of the protein, a hallmark of misfolding diseases. Recently epigenetic modifiers have been shown to alleviate various misfolding diseases suggesting that they may be beneficial for correcting the trafficking defect associated with the ΔF508 mutation of CFTR. We now show that treatment with such epigenetic modifiers can alleviate the ER retention of ΔF508-CFTR to deliver a functional channel to the cell surface in both a culture model (CFBE41o-) and in human primary bronchial epithelial cells isolated from CF patients homozygous for the ΔF508 mutation. Additionally we have identified a single member of a large family of enzymes as the key molecular target of these small molecule epigenetic modifiers. siRNA-mediated knockdown of this protein results in robust correction of the trafficking defect and robust cell surface chloride channel activity. We believe that this correction is a result of an overall alteration of the proteostatic environment of the cell such that multiple CFTR linked pathways are altered to favor increased ER stability, ER export, cell surface delivery and channel activity. DMHutt is supported by fellowships from the Canadian Institutes for Health Research and the Canadian Cystic Fibrosis Foundation.