Cystic Fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The disease affects multiple organs, including the lungs, intestines, liver, pancreas, and male genitals. In CF, mucus production is elevated and causes many complications in this disease. Lung disease produces most CF morbidity and mortality. Major progress has been made over the past decade in CF drug development. Approximately 90% of patients now benefit from mono or combination therapy of several CFTR potentiators and correctors. However, these compounds neither permanently cure the disease nor address the unmet need of the 10% null mutation carriers. In addition, for all CF patients, the increased longevity with these new CF drugs may present with new challenges in organs outside of the lungs. Gene editing therapy represents a promising strategy to permanently cure the disease.

In 2019, we reported efficient gene editing on major CFTR loci in human induced pluripotent stem cells (iPSC). In 2020, we reported the development of miCas9 that has extraordinary homology directed repair capacity. Built on these two discoveries, we propose development and optimization of this novel miCas9 variant as a candidate for in vivo gene-editing therapy of CF.