CF is a life-shortening genetic disease that affects an estimated 70,000 people worldwide, including approximately 65,000 in the United States and Europe. There is no known cure for CF and the predicted median age of survival in the United States is approximately 41 years.
The prevalence of CF is expected to increase at an average annual rate of 0.8% between now and 2023. The main driver of this growth is increased life expectancy due to the introduction of disease modifying therapies that extend life. CF patients typically require lifelong treatment with multiple daily medications and frequently require hospitalization and potentially lung transplant.
CF is caused by mutations in the gene that encodes CFTR, a chloride channel that regulates the movement of salt and water into and out of cells in organs such as the lungs, pancreas and gastrointestinal tract. CF occurs only in patients with two defective copies, or alleles, of the CFTR gene.
In CF patients, defective CFTR cannot perform its normal function, which results in the buildup of thick mucus in several vital organs. Lung disease is the most critical manifestation of CF, characterized by airway obstruction, infection and inflammation that allows bacteria to grow unfettered and impairs the lung’s immune system.
More than 90% of all CF patients die of respiratory failure. In the pancreas, damage caused by CF leads to diabetes and the buildup of mucus prevents the release of digestive enzymes that help the body break down food and absorb important nutrients. In the gastrointestinal tract, the thick mucus contributes to further impairment of nutrient absorption.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein in animals that is encoded by the CFTR gene. The CFTR protein forms a chloride channel that manage the flow of salt and water into and out of cells.
There are more than 1,800 known mutations in the CFTR gene, including the most prevalent mutation, the F508del mutation, found in 86% of all CF patients in the United States and Europe. In the F508del mutation, the deletion of an amino acid results in misfolded CFTR that remains unstable and is targeted for degradation by chaperone proteins, or cellular processes.
As a result, not enough CFTR reaches, or "traffics," to the cell surface. F508del is therefore referred to as a trafficking mutation. In the United States, approximately 47% of CF patients are homozygous and have two copies of this mutation, and 39% are heterozygous and have one copy.
Other CFTR mutations include gating mutations, such as G551D, found in approximately 4% of all CF patients. Cells with gating mutations have normal amounts of CFTR at the cell surface, but the channels fail to open, or "gate" properly.