(657) Combinatory treatment of LAU-7b with triple therapy results in improved lung physiology and restored fatty acid and lipid levels

Background: Cystic fibrosis (CF) is an autosomal recessive genetic disease that affecting more than 100,000 individuals worldwide [1]. It is caused by mutations in the gene encoding CFTR, a cAMP-activated ATP-gated chloride and bicarbonate channel and water transport regulator. CFTR localizes in the plasma membrane of epithelial and other cells, but mutations can disrupt the biosynthesis and trafficking of CFTR or reduce its function at the membrane. The most frequent mutation, (70% of all mutations), is the deletion of phenylalanine at position 508 (F508del), which leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. Treatment with the triple combination drug therapy, TRIKAFTA^®, has become the standard of care, therefore, we wanted to assess if LAU-7b can complement the efficacy of TRIKAFTA®.

Methods: To examine the effect of combining LAU-7b oral treatment and triple therapy (formulation containing all three modulators in TRIKAFTA®) on lung function, a F508deltm1EUR mouse model displaying lung abnormalities relevant to human CF was used. We assessed lung physiology by testing airway resistance using a Buxco plethysmograph system, ventilators, and nebulizers. Lung histopathology was evaluated using hematoxylin and eosin-stained tissue. Lipid oxidation was measured fluorometrically, while protein oxidation and ceramides were measured by ELISA. Fatty acids were analyzed by gas chromatography.

Results: Repeat dose, oral treatment in CF mice with combined LAU-7b and triple therapy compared to triple therapy alone resulted in significantly improved lung physiology, ameliorated histopathology as defined by decreased airway hyperplasia, and a decrease in lipid oxidation. Moreover, the fatty acids profile and the very long chain ceramides/long chain ceramides ratio (VLCC/LCC) were corrected.

Conclusions: Combination of triple therapy with LAU-7b oral treatment significantly improved multiple markers of CF lung disease including lung function and airway histopathology, in the F508del^tm1EUR mouse model. The results in mice suggest a potential clinical benefit of the combinatory treatment of LAU-7b and TRIKAFTA®, for people with CF.

Acknowledgements: We thank Dr. Bob Scholte for generously providing us with the Cftrtm1EUR mouse model (C57BL/6J), heterozygous for the F508del Cftr mutation, obtained from the Erasmus Medical Center (Rotterdam, Netherlands). We want to acknowledge Laurent Pharmaceutical Inc. for having generously provided the clinical capsules used for treatment of Cftrtm1EUR F508del mice and their littermate controls. This work was supported by IGA_LF_2021_019, the European Regional Development Fund - Project ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868), and PSVT2B grant from MESI and Laurent Pharmaceuticals Inc.

References: 1. Shteinberg, M., et al., Cystic fibrosis. The Lancet, 2021. 397(10290): p. 2195-2211.