Refining Phenotypic Assays of CFTR Modulators for Precision Cystic Fibrosis Medicines

TOPICAL COLLECTIONS

Guest Editors

Shafagh Waters

University of New South Wales

I initiated the molecular and integrative Cystic Fibrosis (miCF) Research program in August 2016 at UNSW, Sydney, Australia. My laboratory has established a bioresource of matched airway and gut organoids from people with cystic fibrosis. To date, we have created primary airway cells from over 200 CF patients, 50 of which have matched gut organoids. We implemented a multi-analytical platform of in silico molecular dynamics simulations, in vitro organoid-based CFTR functional assays and an array of ‘omics technologies’ to understand epithelial developmental and the role aberrant processes play in progression and pathophysiology of CF disease. My current research has a strong translational focus in three key areas of (i) stem cell biology involving disease modeling (ii) prognostic and diagnostic exosomal biomarker discovery for CF related diabetes, and (iii) CFTR restoring therapeutics in patient derived organoids using a variety of delivery approaches.

Christine Bear

University of Toronto

My laboratory has published >160 papers including those focusing on the molecular basis for disease caused by Cystic Fibrosis and the mechanism underlying therapeutic rescue by small molecule modulators. My lab has also defined putative mechanisms underlying modification of Cystic Fibrosis disease severity by genetic modifiers-namely, the amino acid transporter, SLC6A14. We have been instrumental in developing methods for CF disease and therapy modeling using stem cell derived tissues through the creation of novel phenotypic tools for interrogating ion channel function for these tissues. Most recently, in order to enable genome/transcriptome/phenome wide interrogation of patient-specific barriers to therapeutic rescue, I initiated funding for and now, co-direct the unique bioresource, called the CFIT (Cystic Fibrosis Program for Individualized Therapy), 100 cell line project. This bioresource is comprised of airway samples and paired iPSC lines from more than 100 donors (with or without pre-existing disease) with links to whole genome sequence and clinical data. Our program enables CF therapy discovery by academic and industry groups as well as the training of highly qualified personnel.

Collection Overview

Phenotypic assays of CFTR channel activity in patient-derived tissues have been instrumental in the development of effective therapies targeting basic defects caused by the major mutation: F508del-CFTR and multiple missense mutations. Such preclinical studies involve bioelectric measures of CFTR channel responses to modulators in primary respiratory epithelial cultures. More recently, three-dimensional tissue models called organoids have also been found to capture mutation specific responses to approved and emerging modulators. Importantly, new models and assays are being developed to meet future challenges. For example, researchers in the field envision the need for in-vitro and ex-vivo phenotypic assays which predict the best modulator (or modulator combination) for each patient of a given genotype. In addition, robust high-throughput phenotypic platforms are required for discovery of interventions for individuals for which effective therapies are still required.

This collection captures emerging technology development in this area as well as methods for multiplexing patient and tissue specific responses to approved therapies and novel interventions. Specifically, we will show in-vitro and in-vivo protocols that promise to enhance the fidelity of capturing patient specific responses to modulators in the future. We will also show novel methods with the potential to conduct high-content phenotypic screens necessary for therapy discovery.