Interrogating the role of miRNA in predicting responses to novel modulator therapies in children with Cystic Fibrosis

Cystic Fibrosis (CF) is a hereditary condition effecting over 80.000 people worldwide with the highest incidence occurring amongst the Irish population. There is no cure for CF however the arrival of a new era of medication that can correct Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) mutations, the basic defect that causes the disease, has had a life-changing impact on many. Whilst these new modulator drugs can now reach over 90% of CF sufferers unfortunately there are individuals who will fail to respond to modulator therapy in addition to those who are not eligible to receive these drugs due to their ultra-rare mutations. In this study we will pair up with the clinical teams working on the real-word RECOVER study which is examining the day-to-day effects of the latest triple combination modulator Kaftrio®. We will create a patient specific lab model of CF lung disease to investigate variable Kaftrio® response using induced pluripotent stem cells (iPSC). These cells are generated by "reprogramming" cells from a blood sample into stem cells enabling them to form any cell type in the body and have been used to model genetic lung disease by researchers in recent years. Firstly, we propose to direct iPSC towards lung cells grown as 3D clusters to model CF lung disease from individuals identified as high and low responders to Kaftrio®. We then aim to examine small pieces of genetic material called microRNA (miRNA) known to be altered in CF to assess their impact in varying responses to Kaftrio®. Additionally, we propose to perform further experiments to see if we can improve modulator drug response by manipulation of altered miRNA or the genes that they can control. These findings may have value in drug response predictions, enhancement of existing drug action and assist in expanding access to these drugs.

Award Date

30 June 2022

Award Value

€781,767

Principal Investigator

Dr Irene Oglesby

Host Institution

Royal College of Surgeons in Ireland

Scheme

Emerging Investigator Awards 2022