Rewriting CFTR to cure cystic fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Although F508del is the most frequent mutation, there are in total 360 confirmed disease-causing CFTR mutations, impairing CFTR production, function and stability. Currently, the only causal treatments available are CFTR correctors and potentiators that directly target the mutant protein. While these pharmacological advances and better symptomatic care have improved life expectancy of people with CF, none of these treatments provides a cure. The discovery and development of programmable nucleases, in particular CRISPR nucleases and derived systems, rekindled the field of CF gene therapy, offering the possibility of a permanent correction of the CFTR gene. In this review we will discuss different strategies to restore CFTR function via gene editing correction of CFTR mutations or enhanced CFTR expression, and address how best to deliver these treatments to target cells.

Keywords: Base editing; Cystic fibrosis; Delivery vehicles; Ex vivo gene editing; Gene editing; Gene therapy; In vivo gene editing; Prime editing; Super-exons.