Multi-pathway approach for the correction of CF

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 base pair 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. Many efforts have been centered on the idea of correcting ΔF508 by directly targeting the ΔF508 channel with small molecules (pharmacological chaperones). More recently, global alterations of the cellular proteostasis environment by small molecule approaches or biologics including siRNA to key components of protein folding environments have been successful in correcting many misfolding diseases, supporting a role for a multi-pathway approach in the correction of these pathologies. We now show that correction of ΔF508 stability and function can be achieved by alteration of the multiple homeostasis environments of the cell. Treatment of cells with select modifiers of homeostasis environments leads to an increase in the stability and function of ΔF508 in both lung cells expressing ΔF508 as a transgene as well as in human lung primary cells from a ΔF508 homozygous patient. The level of correction observed in the latter is thought to be corrective for CF. These data lead us to suggest that correction of ΔF508 will require modification of numerous CFTR intersecting pathways in order to regain stability and function in the native tissue environment through modulation of cellular homeostasis pathways. DMH is supported by a fellowship from the Canadian Cystic Fibrosis Foundation.