Cystic fibrosis in the era of effective treatment: Informing targeted therapy and influencing reproductive decision-making

The treatment of cystic fibrosis with small molecule therapies is heralded as a gold standard for the precision medicine era. The past decade in CF research has seen the advent of variant-specific therapies that are able to correct the underlying defect responsible for disease. The eventual goal of providing effective therapy to all individuals with CF is dependent upon the ability to estimate potential clinical improvements attributable to increases in CFTR function. Many other genetic diseases are also beginning to see advances in treatment that address the underlying disease mechanism. This, combined with the ever-increasing availability of genetic screening, means that it is vital for the medical genetics community to understand how these new therapies are affecting people’s views and decisions. Taking into account a changing disease landscape is essential when developing screening and counseling protocols, as well as recommendations for carrier testing. Cystic fibrosis provides a paradigm to understand how precision treatment is being applied in the clinic and beyond

Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.

CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function 1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit