Background Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Defective CFTRs affect cells that produce mucus, sweat, and digestive juices, making these cells to produce fluids that become thick and sticky, limiting the ability to breath and resulting in persistent lung infections. CF affects 70,000 children and adults worldwide.
Symptoms vary and can include cough, repeated lung infections, inability to gain weight, and fatty stools. Treatments may ease symptoms and reduce complications, but there is no cure to date. Small-molecule modulators were recently approved, but they only partially restore CFTR function. Therefore, there is a need for the development of additional therapeutic modalities to improve CFTR function.
Technology Lubiprostone (Amitiza®) was developed and approved by the FDA in 2006 for the treatment of chronic idiopathic constipation. Investigators at National Jewish Health have shown that lubiprostone can be an effective CFTR activator in primary airway epithelia. They have obtained preliminary data showing that lubiprostone used in combination with FDA-approved CFTR modulators can increase the function of 508del and other CFTR mutations.
For example, co-treatment of F508del epithelia with VX-445/661/770 and lubiprostone restored acute CFTR activity by ~60% compared to treatment with VX-445/661/770 alone. The increase in CFTR activity after chronic co-treatment of lubiprostone with current CFTR modulators demonstrates the therapeutic potential of lubiprostone for the treatment of CF caused by F508del as well as gating and residual function mutations.
Potential Applications Use of CFTR activators combined with CFTR modulators as a treatment of CF in patients with CFTR residual function mutations.
State of Development The use of CFTR activating compounds in the treatment of CF is currently being evaluated using in vitro models of the airway epithelium utilizing cells derived from CF patients. Activators are being testing in the presence and absence of currently available FDA approved CFTR modulator therapies.
Bratcher, et. al. Lubiprostone as a novel, receptor-mediated activator of CFTR in the airway. In vitro evidence for treatment of F508del and other CFTR mutations. Abstract. Supplement to Pediatric Pulmonology, 2020.
Shaughnessy CA, Yadav S, Bratcher PE, Zeitlin PL. Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway. Am J Physiol Lung Cell Mol Physiol. 2022 Mar 1;322(3):L305-L314. doi: 10.1152/ajplung.00388.2021. Epub 2022 Jan 12. PMID: 35020527
Licensing Status This technology is available for license.
For Further Information, Contact: Emmanuel Hilaire, PhD Director Technology Transfer Office National Jewish Health 1400 Jackson Street, Room M206b Denver, CO 80206 Voice: 303.398.1262 HilaireE@njhealth.org