Therapeutic correctors of Cystic Fibrosis

Advantages

• Small molecule correctors of mutated chloride ion channels manage cystic fibrosis at a functional level.
• Effective at nanomolar concentrations

Technology Details

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis trans-membrane conductance regulator gene (CFTR) that encodes a cAMP-regulated chloride ion channel expressed on the surface of epithelial cells. Approximately 90% of CF patients have a ∆F508 CFTR mutation and it is believed that only 10-15% of the ∆F508-CFTR needs to be corrected in order to restore CFTR function. The small molecules that rescue defective CFTR are called correctors and those identified to date have not been potent enough to be considered good drug candidates.
Researchers at The University of British Columbia and McGill University have identified potent, nanomolar concentration, CFTR correctors from a library of marine natural products. They were identified, using a novel screening assay to detect ∆F508-CFTR trafficking defect correctors. The screen uses 3 haemaglutinin tags (3-HA) and the tagged CFTR is inserted into Baby Hamster Kidney cells (BHK). The appearance of ∆F508-CFTR or wild-type CFTR at the cell surface is monitored with an anti-HA antibody and a fluorescent secondary antibody in a 96-well plate format. Hits are compounds that give a response 3 standard deviations above the control value. These correctors are considerably more active than any previously reported correctors and they represent exciting drug leads and cell biology tools.
The existing solutions for Cystic Fibrosis address only the treatment of symptoms such as mucous accumulation and infection. The use of correctors to traffic ∆F508-CFTR to the membrane would manage the disease at a functional level.