A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience

David Sheppard: Precision Medicine for Cystic Fibrosis: Matching Modulators to Mutations

Abstract: Since 2019, the highly effective orally-bioavailable drug therapy elexacaftor-tezacaftor-ivacaftor, which targets pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), has transformed the treatment of cystic fibrosis (CF) for most, but not all people with the disease. CFTR is a highly polymorphic human gene with > 2,100 variants many affecting residues important for CFTR expression and/or function as an epithelial anion channel. Although most variants are extremely rare, there is one notable exception: F508del, one copy of which is carried by 90% of people with CF worldwide.
To assist therapy development, variants are classified into six classes by their mechanism of CFTR dysfunction. Few variants cause CFTR dysfunction by a single mechanism. The majority have multiple mechanisms of CFTR dysfunction. Elexacaftor-tezacaftor-ivacaftor consists of two types of drugs.
Elexacaftor and tezacaftor are CFTR correctors, which overcome the misfolding and misassembly of CFTR domains to deliver CFTR proteins to the plasma membrane, whereas ivacaftor is a CFTR potentiator that enhances CFTR channel gating. Based on the efficacy and safety of elexacaftor-tezacaftor-ivacaftor and undisclosed in vitro data, in 2020, the FDA extended the use of elexacaftor-tezacaftor-ivacaftor from F508del to 177 additional CFTR variants, while in 2023, following additional clinical trials, the therapy became available to children aged ≥ two years with F508del and one of the additional CFTR variants. In this seminar, I will highlight single-channel studies investigating (i) how selected rare CFTR variants cause CFTR dysfunction and respond to CFTR modulators and (ii) mechanistic studies of F508del-CFTR rescue by elexacaftor-tezacaftor-ivacaftor.

Dr Yong Li: Teaching an old dog a new trick – by supercharging its platelets with therapeutic molecules to treat myocardial infarction

Abstract: Platelets have been well known to release its diverse bioactive cargos stored in its granules in reaction to acute tissue injury to initiate a complex cascade of inflammatory and reparative process after acute myocardial infarction (MI). However, how these releasate contributes to the cardiac remodelling is still poorly understood. We seek to create a murine MI model by surgical ligation of the left anterior descending branch of its coronary artery (LAD) to test what effects will the platelet releasate have on the mouse left ventricular remodelling when directly injected into the ischemic myocardium. We also test whether delivery by iv injection of mouse platelets super-charged with several grow factors can affect the outcome of remodelling in an ischemia-reperfusion MI model. The ultimate goal is to develop super-platelets by bio-engineering and use them as vehicles to deliver therapeutic molecules to ischemic myocardium as a novel MI treatment.