Human nasal epithelial organoids as a non-invasive, personalized model for predicting effectiveness of CFTR modulators in cystic fibrosis patients

DESCRIPTION provided by applicant The discovery of the single gene CFTR cause of cystic fibrosis CF has been transformational focusing treatment on modulator drugs that restore function of the CFTR gene product CFTR andquot correctorsandquot enhance transport of mutant protein to the cell membrane and CFTR andquot potentiatesandquot activate mutant protein that does get to the membrane The FDA approved potentiate drug invocator has resulted in remarkable quality of life improvements for the of the CF population with specific responsive CFTR mutations Mixed results but none approaching the invocator outcome have been achieved for the remaining majority of the CF population The major hurdle is that over different CFTR gene mutations have been identified some relatively frequent and others quite rare so that available cell based assays for testing potential drugs have unpredictable relevance for an individual with CF In the absence of cell based ex vivo or any known in vivo assays there are no reliable predictors of clinical outcomes specific to the individual leading to arduous potentially harmful trial and error drug treatment without any predictive basis for success This STTR proposal seeks to overcome this hurdle by developing a personalized ex vivo minimally invasive and predictive screening assay for CFTR modulator activity Cells from a single minimally invasive nasal biopsy are cultured to generate many nasospheres three dimensional cultures that remarkably and relatively quickly replicate the nasal epithelium with a ciliated linig and a mucus barrier Each nasosphere constitutes an ex vivo organoid a replica of the donorandapos s nasal cells amenable to drug testing detailed probing of outcome measures and precise measurement of restored CFTR activity The ability to generate many nasospheres from a single biopsy allows combinatorial drug testing of restored CFTR activity for that person and the potential to optimize all available drugs for an individual Accepted outcome measures that correlate with restored CFTR activity are nasosphere volume change and cilia beat frequency Further we propose novel measurements of nasosphere mucus viscoelasticity using particle tracking microbeads rheology which reflects changes in mucus hydration and is a predictor of cilia propulsion of mucus and mucus clearance Phase success will lead to Phase in which nasosphere assay outcome measures will be correlated with in vivo drug treatment efficacy Success in Phase will lead to commercialization of the nasosphere assay and associated data analysis to enable urgently required personalized reliable and predictive treatment decisions for individuals with CF PUBLIC HEALTH RELEVANCE Individuals with cystic fibrosis face two realities the extreme diversity in known CFTR gene mutations and the extreme non uniformity in response to CFTR modulator drugs This project establishes proof of principle of a novel minimally invasive personalized assay to assess CFTR recovery to all proposed drugs