The discovery of pharmacologic cystic fibrosis transmembrane conductance regulator (CFTR) modulators has transformed the landscape for cystic fibrosis (CF) treatment worldwide. A substantial fraction of CF patients can benefit from the small molecule ivacaftor and its partner drugs. However, around 10 percent of patients are not eligible for such therapy, either because their CFTR genotype is refractory to existing drugs or because they cannot tolerate modulator therapy. For these patients, there is an urgent need for alternative strategies to restore CFTR function.

Our goals for this project are to (1) develop base editors corresponding to CFTR mutations that are currently beyond the reach of ivacaftor and its partner drugs, (2) develop a pipeline for cell-specific assessment of the editing performed by the CF-specific base editors developed in Goal 1, and (3) use an animal model of CF for pre-clinical testing of approaches developed and refined in Goals 1 and 2.

This project is part of the research program Advancing Delivery of Novel Genome Editing Enzymes to Correct Orphan CF Mutations (overall PI: Urnov). Also see Development of novel technologies for delivery of base editors to the airway epithelium.