WS01.2 QR-010, an RNA therapy, restores CFTR function using in vitro and in vivo models of ΔF508 CFTR

Abstract

CF is caused by mutations in the CFTR gene, encoding an apical cell-surface chloride channel expressed mainly in epithelial cells. The most prevalent CFTR mutation is a deletion of three base pairs leading to loss of phenylalanine at position 508 (ΔF508). QR-010 is an investigational single-stranded, chemically modified RNA oligonucleotide designed for inhalation to repair ΔF508 CFTR mRNA, resulting in translation of wild-type (WT) CFTR. Methods In vitro – We investigated whether QR-010 restored CFTR function in cell cultures homozygous for ΔF508 CFTR using an Ussing chamber assay with primary human bronchial epithelial cells (HBEs) and a chloride efflux assay with a halide-sensitive fluorescent indicator, MQAE. In vivo – In ΔF508 mice, nasal potential difference (NPD) and saliva secretion assay (SSA) were used to investigate if QR-010 could restore CFTR function after intranasal and orotracheal administration. Results Treatment with QR-010 significantly improved chloride efflux compared to treatment with a scrambled oligonucleotide in the MQAE assay. The Ussing chamber assay showed that QR-010 increased CFTR-specific current in HBEs compared to untreated HBEs. QR-010 significantly improved the total intranasal CFTR-mediated chloride transport in ΔF508 mice to ∼80% of WT level as assessed by NPD. In addition, QR-010, compared to saline, significantly improved CFTR-mediated saliva secretion in female ΔF508-CFTR mice after 2 doses to ∼80% of WT levels. The increased saliva secretion was seen up to 14 days following the last dose. Elaborated studies are currently ongoing. Conclusion QR-010 restores CFTR function in human cells in vitro as well as in ΔF508 mice in vivo.