Rapid therapeutic advances in CFTR modulator science

Abstract

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding the cystic fibrosis transmembrane conduction regulator (CFTR) protein. Loss of CFTR function disrupts chloride, bicarbonate and regulation of sodium transport, producing a cascade of mucus obstruction, inflammation, pulmonary infection, and ultimately damage in numerous organs. Established CF therapies treat the downstream consequences of CFTR dysfunction and have led to steady improvements in patient survival. A class of drugs termed CFTR modulators has recently entered the CF therapeutic landscape. These drugs differ fundamentally from prior therapies in that they aim to improve the function of disease-causing CFTR variants. This review summarizes the science behind CFTR modulators, including their targets, mechanism of action, clinical benefit, and future directions in the field. CFTR modulators have dramatically changed how CF is treated, validated CFTR as a therapeutic target, and opened the door to truly personalized therapies and treatment regimens.

Keywords: CFTR; cystic fibrosis; ion transport; modulator.

Figure 1

CFTR variant classes discriminated by presence or absence of CFTR at the plasma membrane. Left: CFTR variants that result in minimal or absent CFTR in the plasma membrane. The red stars represent defects in transcription, translation, or protein folding. Examples within each group are listed below in parentheses. Right: CFTR variants with significant levels of CFTR in the plasma membrane. The red arrow represents reduced levels of functional CFTR localizing to the plasma membrane (with a non‐canonical splice defect represented). The red stars represent CFTR variants with normal levels in the plasma membrane, but with defective gating or conduction. Examples within each group are listed below in parentheses