KIT2014 is a cell-permeable cAMP modulating peptide that disrupts the interaction of PI3Kgamma with its partner, protein kinase A (PKA), leading to type 3 and 4 phosphodiesterases (PDE3/4) inhibition and, in turn, to enhanced cAMP responses within the cell. Localized cAMP elevation potentiates both the stabilization and opening of cystic fibrosis transmembrane conductance regulator (CFTR) protein channels at the plasma membrane. KIT2014 is currently being investigated for the treatment of cystic fibrosis (CF) as an add-on inhalation therapy to the current standard of care, enabling improved efficacy by directly impacting mucus hypersecretion, airway inflammation and bronchoconstriction, issues that are inherent to CF. When inhaled, KIT2014 increases cAMP locally in bronchial epithelial cells to promote the opening of CFTR chloride channels, which are key to mucus hydration, whilst in lung smooth muscle and immune cells, cAMP elevation limits bronchoconstriction and neutrophil infiltration. In CF patients, treatment with KIT2014 is believed to restore the function of CFTR mutants by potentiating the effects of CFTR modulators (Ghigo et al., Science Translational Medicine 2022).
Cystic fibrosis (CF) is a rare genetic disease that causes airway mucus obstruction and persistent lung infections that, over time, limits the patient’s ability to breathe. In people with CF, a defective gene (cystic fibrosis transmembrane conductance regulator, CFTR) causes a thick, sticky build-up of mucus in the lungs, pancreas, and other organs. People with the disease inherit two copies of the defective CFTR gene, one from each parent. In the lungs, the mucus clogs the airways and traps bacteria, leading to recurrent infections, lung inflammation and damage, and, eventually, respiratory failure. Patients with CF are treated with specific drugs to address the underlying molecular defect (CFTR modulators), physiotherapy, postural drainage, and antibiotics, which together help remove mucus from their lungs, improve their ability to breathe, and address chronic lung infections. Despite the recent therapeutic advances, CF patients are still in need of treatments with improved efficacy and safety (Mall et al. 2019).
Mode of therapy
Orphan Drug Designation