A multimodal iPSC platform for cystic fibrosis drug testing

Andrew Berical, Rhianna E. Lee, Junjie Lu, Mary Lou Beermann, Jake A. Le Suer, Aditya Mithal, Dylan Thomas, Nicole Ranallo, Megan Peasley, Alex Stuffer, Katherine Bukis, Rebecca Seymour, Jan Harrington, Kevin Coote, Hillary Valley, Killian Hurley, Paul McNally, Gustavo Mostoslavsky, John Mahoney, Scott H. Randell and Finn J. Hawkins ()
Additional contact information
Andrew Berical: Center for Regenerative Medicine of Boston University and Boston Medical Center
Rhianna E. Lee: University of North Carolina at Chapel Hill
Junjie Lu: Cystic Fibrosis Foundation
Mary Lou Beermann: Center for Regenerative Medicine of Boston University and Boston Medical Center
Jake A. Le Suer: Center for Regenerative Medicine of Boston University and Boston Medical Center
Aditya Mithal: Center for Regenerative Medicine of Boston University and Boston Medical Center
Dylan Thomas: Center for Regenerative Medicine of Boston University and Boston Medical Center
Nicole Ranallo: Center for Regenerative Medicine of Boston University and Boston Medical Center
Megan Peasley: Cystic Fibrosis Foundation
Alex Stuffer: Cystic Fibrosis Foundation
Katherine Bukis: Cystic Fibrosis Foundation
Rebecca Seymour: Cystic Fibrosis Foundation
Jan Harrington: Cystic Fibrosis Foundation
Kevin Coote: Cystic Fibrosis Foundation
Hillary Valley: Cystic Fibrosis Foundation
Killian Hurley: Education and Research Centre, Beaumont Hospital
Paul McNally: RCSI University of Medicine and Health Sciences
Gustavo Mostoslavsky: Center for Regenerative Medicine of Boston University and Boston Medical Center
John Mahoney: Cystic Fibrosis Foundation
Scott H. Randell: University of North Carolina at Chapel Hill
Finn J. Hawkins: Center for Regenerative Medicine of Boston University and Boston Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.

Date: 2022
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DOI: 10.1038/s41467-022-31854-8

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