, Volume 1, Issue 3, pp 223-238
Date: 21 Aug 2012

Cystic Fibrosis and the Use of Pharmacogenomics to Determine Surrogate Endpoints for Drug Discovery

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Cystic fibrosis (CF) is caused by a mutation in the CFTR gene, encoding a chloride channel. For the most common mutation, ΔF508, the basis of the deficit is the failure of the mutant CFTR channel protein to traffic properly to the apical plasma membrane of the affected epithelial cell. The trafficking failure results in loss of the cyclic adenosine monophosphate (cAMP)-activated chloride channel function of the CFTR protein in the plasma membrane. The lung is the principal site affecting patient morbidity and mortality in CF. The main reason is that the CF airway epithelial cells also secrete high levels of the proinflammatory cytokine interleukin (IL)-8, resulting in massive cellular inflammation, infection, tissue damage and lung destruction. The relationship between the trafficking defect, the loss of chloride channel activity, and inflammation is not known. However, gene therapy of CF lung epithelial cells with the wild-type CFTR gene can repair the chloride channel defect, as well as suppress the intrinsic hypersecretion of IL-8. Repair of both defective channels and high IL-8 secretion can also be effected by treatment with the candidate CF drug CPX, which is in clinical trials in CF patients. CPX acts by binding to the mutant CFTR protein, and helps the protein to mature and gain access to the plasma membrane. CPX also suppresses the synthesis and secretion of IL-8 from CF epithelial cells, presumably by virtue of its repair of the trafficking defect of mutant CFTR. To guide pharmacogenomic experiments we have therefore hypothesized that the genomic signature of CF epithelial cells treated with CPX should resemble the signature of the same cells repaired by gene therapy. We have developed two algorithms for identifying genes modified by repair of CFTR defects. The GRASP algorithm uses a statistical test to identify the most profoundly changing genes. The GENESAVER algorithm allows us to identify those genes whose pattern of expression changes in-phase or out-of-phase with IL-8 secretion by CF cells. For the latter algorithm we modified IL-8 secretion from CF cells by treatment with wild-type CFTR, with CPX, or by exposure to bacteria. The results have supported the hypothesis, and have provided a basis for considering the common pharmacogenomic expression signature as a surrogate endpoint for CF drug discovery. Significantly, the nature of the hypothesis, as well as the algorithm developed for this study, can be easily applied to pharmacogenomic studies with other goals.