Cellular model for personalized CFTR-directed therapeutics.

Project Abstract Summary This proposal is a NHLBI RFARto develop and validate a novel human cell based diagnostic tool for predicting individual cystic fibrosisCFpatient responses to drugs that improve the function of mutated forms of the cystic fibrosis transmembrane conductance regulatorCFTRproteinLargescale in vitro expansion of human nasal epithelial cells is now feasibleThe primary cellswhen differentiated as air liquid interface culturesALIrecapitulate a patient specific CFTR phenotype and provide a sensitive and reproducible platform for testing CFTR directed therapeuticsTransepithelial ion transport is a direct measure of CFTR function and in vitro demonstration of improved function of mutated CFTR has been shown to predict clinical benefit in specific patientsNasal epithelial cells are collected from CF subjectsculturedand cryopreserved to generate a bank of cells of known CFTR genotypeCells are expandedseeded onto filter supports for ALI cultureup tocultures subjectdifferentiatedtested for CFTR expression and activityThe immediate goals of this project are to use the primary HNE cell cultures toestablish reproducibility of inter patient CFTRdrug response variabilitydetermine if in vitro responses predict long term in vivo clinical benefitandidentify rare mutations that respond to existing CFTR modulatorsThe long term goal is to show that this in vitro human cell model predicts individual patient responses to CFTR directed therapeutics and to develop a diagnostic platform to guide optimization of personalized therapies for all CF patients