Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

Abstract

Background: Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target different variants to improve lung function, but large variability in response exists and current therapies do not address all CF-causing variants highlighting an unmet need. Alternative epithelial ion channels such as SLC26A9 could compensate for CFTR dysfunction, providing a therapeutic target that benefits all individuals with CF. Method: We investigate the relationship between SLC26A9 and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Results: SLC26A9 rs7512462 CC genotype is associated with greater lung function in individuals with minimal function variants (for which there are currently no approved therapies; p=0.002); and gating (p=0.03) and p.Phe508del/ p.Phe508del (p=0.009) genotypes upon treatment with CFTR modulators. Analogously, p.Phe508del/p.Phe508del human nasal epithelia with CC after triple combination modulator treatment show greatest CFTR function (p=8x10-4). Beyond CF, rs7512462 is associated with lung function in the UK Biobank (meta-p=2.74x10-44) and in COPD (min p=0.007). Conclusion: These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases such as COPD.