Cystic Fibrosis (CF) is the most common lethal genetic disorder in Ireland with over 1,500 people affected. The disease is caused by mutations in the CFTR gene of which there are currently >2,000 recognised mutations. The discovery of CFTR modulator drug therapy has radically altered how we might treat CF using precision medicine. Modulator therapy can now reach up to 90% of people with CF however, inter-individual variability in modulator efficacy poses a significant problem in the clinic. Several preclinical models of CF exist for in-vitro drug testing, but none are both lung specific and reflect individual patient’s genetic background so, for better treatment for CF we need better tools. Here we aim to utilise a recently developed human in-vitro system for the derivation of lung-specific organoids from induced pluripotent stem cells (iPSC) from children with CF participating in the ‘real world’ RECOVER study. Patient specific iPSC-derived organoids will be generated from a panel of individuals clinically defined as having the greatest and least improvement in response to the next generation triple combination therapy, Kaftrio®. We hypothesise that miRNA, known to be dysregulated in CF, play a key role in CFTR modulator therapy efficacy and that patient specific iPSC-derived models of Kaftrio® responsiveness can help elucidate this role. Our objective is to examine manipulation of miRNA, mRNA and potential novel targets identified in global expression profiling of miRNA in high and low responders. Forskolin-induced organoid swelling and air liquid interface culture will be then employed to measure lung specific CFTR function and augmentation of modulator therapy response. The use of modulator drugs is still in its infancy. This study will create knowledge regarding their biological impact, assist prediction of individual responses and develop novel strategies to enhance efficacy to maximise the potential benefit of these drugs for all CF sufferers.
