Elexacaftor/Tezacaftor/Ivacaftor Supports Treatment for CF with ΔI1023-V1024-CFTR

Abstract

Cystic Fibrosis (CF) is a common genetic disease in the United States, resulting from mutations in the Cystic Fibrosis transmembrane conductance regulator (cftr) gene. CFTR modulators, particularly Elexacaftor/Tezacaftor/Ivacaftor (ETI), have significantly improved clinical outcomes for patients with CF. However, many CFTR mutations are not eligible for CFTR modulator therapy due to their rarity. In this study, we report that a patient carrying rare complex CFTR mutations, c.1680-877G>T and c.3067_3072delATAGTG, showed positive clinical outcomes after ETI treatment. We demonstrate that ETI was able to increase the expression of CFTR harboring c.3067_3072delATAGTG in a heterologous system. Importantly, patient-derived nasal epithelial cells in an air-liquid interface (ALI) culture showed improved CFTR function following ETI treatment. These findings supported the initiation of ETI with the patient. Retrospective studies have suggested that the patient has shown small but steady improvement over the past two years in several clinical metrics, including lung function, body mass index (BMI), and sweat chloride levels. Our studies suggest that ETI could be beneficial for patients carrying c.3067_3072delATAGTG.

Keywords: CFTR; CFTR modulators; Cystic Fibrosis (CF); I1023-V1024; nasal epithelial cells; tTheratyping.

Figure 1

ETI improved the lung function and body development in the patient. Longitudinal observations of percent predicted FEV1 (ppFEV1) and Body Mass Index (BMI), indication of lung function, and body development, respectively, two years before and after ETI initiation. FEV1: Forced Expiratory Volume in one second.

Figure 2

Elexacaftor/Tezacaftor/Ivacaftor improves the expression and function of ΔI1023-V1024-CFTR. (A) Representative images of immunoblotting. As described in the Methods Section, ΔF508-, ΔI1023-V1024, and wildtype (WT) CFTR were transiently overexpressed in HEK 293 cells. Cells were then treated with DMSO (−− or VX-445/661 (2 μM) for 48 h before being harvested. Samples were subjected to immunoblotting to probe for CFTR and Tubulin using specific α-CFTR (CFF 596) and α-Tubulin antibodies, respectively. B and C indicate the CFTR immature band and the mature band, respectively. (B) The band intensity in (A) was quantified using Image Lab v5.0, and the ratio of Band C/(C + B) was determined. Statistical analyses were performed using a Student’s t-test in GraphPad Prism 10.3.1. *** represents p < 0.001. (C) Analysis of CFTR function in response to Forskolin (FSK)/VX-770 in patient-derived nasal epithelial cells (NECs). NECs were cultured on Transwell for 4 weeks to differentiate as described in the Methods Section. Each dot represents one replicate from two independent experiments. Statistical analyses were performed using a Student’s t-test in GraphPad Prism 10.3.1. *** represents p < 0.001.