HLS-Applying EpiX technology to enable ex vivo theratyping using nasal brushing samples from CF patients

Project AbstractTopic code HLSSigni cant progress has been achieved in developing precision therapies for cysticbrosisCFhoweverhighly effective treatments that target the cysticbrosis transmembrane conductance regulatorCFTRare not yet available for every patient with CFTherapeutic efforts have recently focused on correcting the defect resulting from the common Fdel variantas well as many less frequent missense allelesOf the missense variantsmore thanhave been noted inindividuals or fewer worldwideThe rarity of these patients precludes standard randomized controlled trials to test ef cacy of new CFTR therapeutics in the clinical pipelinesThus reliable in vitro cell based models capable of predicting drug ef cacy using patient derived cells to support individualized treatment plans and translational research are essentialPrimary human nasal or bronchial epithelial cells have emerged as strong predictive tools to study rare CFTR variants in a near native contextDespite their outstanding valueprimary nasal or bronchial epithelial cells are difficult to grow and expand using conventional cell culture mediaimpeding their employment in evaluating CFTR targeted precision therapyHere we propose using our patented EpiXcell culture technology to expand airway epithelial cells from nasal brushing samples of CF patients for in vitro human cell based models to predict individual responses to CFTR directed therapeuticsEpiXmedium allows over trillion fold of in vitro expansion like the conditional reprogramming methodwithout using feeder cellsThe expanded cells can be seamlessly integrated into existing downstream differentiation protocols and put into physiological CFTR and mucociliary functional evaluationsEpiXexpanded bronchial epithelial cells maintain CFTR and epithelial sodium channelENaCfunctions even after trillion fold expansionEpiXalso supports quick and efficient expansion of a small number of basal epithelial cellssuch as those derived from nasal brushing samplesto generate hundreds of millions of cellsThe EpiXmedium provides a reliablerobust and easyto use solution that offers significant advantages over current technologies that related to the ultimate goals to identify personalized therapy for CF patients Project Narrative on Relevance to Public Health The most common chronic and lifespan shortening genetic disease afflicting the lung is cysticbrosisCFOverallthere are overpeople in the United States with CFand more thanCF patients worldwideOne inCaucasian newborns are diagnosed with the diseaseSincetwo drugs have been approved by the FDA to treat the underlying chloride channel defect in CFOne of the drugKalydecoivacaftoris approved to treat CF patients with one ofmutations in the CFTR genewhich accounts for aboutcases of CFA second drugOrkambilumacaftor ivacaftorhas been developed to treat patients with the more common homozygous Fdel Fdel CFTR mutationbut clinical gains are modest and adverse side effects have forced some patients to stop taking this medicationBoth drugs cost hundreds of thousands of dollars per patient per year in the United Stateswhich represents $million over the life of an average patient with CFMore thanvariants within CFTR have been observed to dateOf the missense CFTR variantsmore thanhave been noted inindividuals or fewer worldwideThe rarity of these patients precludes standard randomized controlled trials to test ef cacy of new CFTR therapeutics in the clinical pipelinesMoreoverCF patients with the same CFTR mutation exhibit substantial variation in severity of lung disease due to the variations in patientsgenetic make upA drug targeting the same CFTR mutation may result in a range of responseswith some individuals showing significant clinical improvement while others have little to no responseReliable in vitro cell based models capable of predicting drug ef cacy using patient derived cells could help to identify which drug or drug combinations would benefit individual patient the mostSuch personalized precision therapy could reduce public health cost significantly