Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis

Abstract

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function.Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators.Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Crosssectional FEV 1 % predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies.Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV 1 % predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype.Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies

“…This is demonstrated by the example of c.3873G>C. Clinical features of individuals harboring this variant have a large amount of variability. For example, sweat chloride (a metric shown to correlate with disease severity, [ 22 ]) ranges from 35–112 mmol/L in these individuals (CFTR2). This may be explained by variability in the amount of normally spliced transcript between individuals, which would in turn impact the amount of residual CFTR function.…”

“…Allelic heterogeneity makes CF an informative model for the study of genetic disease as ~2,000 variants (CFTR Mutation Database) have been identified in the CFTR gene, ~10% of which are thought to impact splicing (CFTR Mutation Database). Notably, the severity of clinical presentations of CF have been well correlated with the deleteriousness of CFTR variants [ 22 ]. Identifying the disease liability of variants and their specific mechanism of disease has become critical as molecular therapies for CF target the underlying molecular defect, thus applying to select individuals depending on the genetic variants they harbor [ 21 ].…”

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…A report pairing in vitro measurement of CFTR function in cell lines and clinical features demonstrated a strong correlation between CFTR function and sweat chloride concentration, and to a lesser extent but still significant with lung function and pancreatic status (McCague et al, 2019). Correlations between responses in patient-derived specimens and clinical parameters/ biomarkers have been investigated to establish reliable prediction of drug effectiveness.…”

Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

“…Trying to understand the clinical liability of CFTR variants has been in the past years a major task of molecular biologists and clinicians. The results of such commitment are reported in dedicated websites, including those of the Clinical and Functional Translation of CFTR Project (CFTR2) 118,144 and of the French database CFTR-France, and in published clinical observations or functional explorations. 145 CFTR2 data originate from CF patient registries, and include data on genetic analysis, sweat test, and clinical descriptions.…”