CFTR stabilizers: validation of novel therapeutic tools in cystic fibrosis – STABTHER

Cystic fibrosis (CF) is the most common lethal autosomal recessive genetic disease in Caucasian populations. Partial or total loss-of-function of the CFTR chloride channel causes mucus thickness and accumulation in the respiratory and digestive tracts. In lungs, the cycles of infection and inflammation ultimately lead to the destruction of the airway parenchyma, which is the first cause of death in CF patients. Despite new drugs (CF modulators), the therapeutic effect based on daily high doses is still insufficient and all CF patients are not eligible for this treatment. To overcome this therapeutic lack, we propose an innovative therapeutic strategy in complement to CF modulators based on "stabilizers" to increase CFTR protein translation/amount, and enhance its half-life at the apical membrane of endothelial cells. Increasing CFTR amount/stability will lead in higher CFTR channel activity which will modulate CF phenotype. In this context, we have recently designed new oligonucleotide and peptide-based entities showing first promising effects (proof of concept carried out on epitheliums with the most frequent mutation). Our STABTHER project, which involve three teams, aimed to push forward the validation of the oligonucleotide and peptide-based CFTR-stabilizers (alone or in combination) as innovative therapeutics which will thus increase efficiency and/or reduce doses of current administrated CF modulators (Trikafta/Orkambi) (Aim 1). We will also apply both CFTR-stabilizers to other CFTR mutations or to epitheliums also suffering from CFTR-deregulation obtained from CF intestinal cells to determine their full therapeutic potential (Aim 2). Finally, we wish to perform the first de-risking trials with the stabilizing CFTR (toxicology and pharmacokinetic studies) in order to attract pharmaceutical companies (licensing) or investors (start-up creation) (Aim 3). The tools developed in this project will provide proof that it is possible to increase the abundance of CFTR in order to increase the effectiveness of current treatments.