The National Heart, Lung, and Blood Institute (NHLBI) and the Cystic Fibrosis Foundation (CFF) co-sponsored a workshop to identify the research barriers and challenges associated with the application of gene editing therapies for cystic fibrosis (CF) lung disease.
Cystic fibrosis is a recessively inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene. The protein product, CFTR, is an anion channel expressed in the epithelia of numerous organs throughout the body that is responsible for regulating fluid absorption and secretion. In the lungs, mutations in CFTR cause the airway surface liquid to dehydrate, disrupting mucociliary clearance. This leads to the accumulation of mucus, chronic infections and inflammation, and ultimately lung failure.
Significant advances have been made to treat the underlying cause of CF with the creation of therapeutics, known as correctors and potentiators, that target specific mutations in the CFTR protein. However, these therapeutics are not likely to work in all patients, especially those who completely lack expression of the CFTR protein. Furthermore, these therapeutics, while effective, are not able to cure the disease. Patients will still suffer from the disease; experiencing a gradual loss in lung function, mucus buildup, and chronic infection. Thus, there is a critical need to develop novel therapeutics that can be applied to all CF patients. A therapeutic application of gene editing has the potential to permanently correct the genetic mutations that cause CF. However, realizing this goal will be a significant challenge as there are numerous scientific and technical barriers that need to be overcome.
Development and implementation of gene editing therapies for the treatment of cystic fibrosis will require a multidisciplinary approach with significant collaboration between investigators from various scientific backgrounds. To help facilitate future collaborations and identify scientific priorities in the field, the workshop included presentations and discussions on such topics as optimizing gene editing technologies for the lung, mitigating off-target editing, in vitro and in vivo model systems for evaluating safety and efficacy, viral and non-viral delivery vehicles, lung cell populations, overcoming the mucus barrier, and strategies to optimize delivery to the lung. After extensive discussion, the workshop participants made the following recommendations:
Division of Lung Disease, NHLBI