Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease

Amanda Centorame; Daciana Catalina Dumut; Mina Youssef; Martin Ondra; Irenej Kianicka; Juhi Shah; Radu Alexandru Paun; Tomas Ozdian; John W Hanrahan; Ekaterina Gusev; Basil Petrof; Marian Hajduch; Radu Pislariu; Juan Bautista De Sanctis; Danuta Radzioch

doi:10.3389/fphar.2022.876842

Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease

Front Pharmacol. 2022 May 20:13:876842. doi: 10.3389/fphar.2022.876842. eCollection 2022.

Authors

Amanda Centorame^{1

2}, Daciana Catalina Dumut^{1

2}, Mina Youssef², Martin Ondra^{3

4}, Irenej Kianicka⁵, Juhi Shah², Radu Alexandru Paun^{2

6}, Tomas Ozdian³, John W Hanrahan⁷, Ekaterina Gusev⁸, Basil Petrof⁸, Marian Hajduch^{3

4}, Radu Pislariu⁵, Juan Bautista De Sanctis^{3

4}, Danuta Radzioch^{1

2

3

5}

Affiliations

¹ Faculty of Medicine, McGill University, Montreal, QC, Canada.
² Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
³ Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czechia.
⁴ Czech Advanced Technology and Research Institute, Palacky University, Olomouc, Czechia.
⁵ Laurent Pharmaceuticals, Montreal, QC, Canada.
⁶ Department of Biomedical Engineering, McGill University, Montreal, QC, Canada.
⁷ Department of Physiology, McGill University, Montreal, QC, Canada.
⁸ Meakins-Christie Laboratories, The Centre for Respiratory Research at McGill University and the Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Abstract

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding CFTR, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. The therapeutics available for treating CF lung disease include antibiotics, mucolytics, bronchodilators, physiotherapy, and most recently CFTR modulators. To date, no cure for this life shortening disease has been found. Treatment with the Triple combination drug therapy, TRIKAFTA^®, is composed of three drugs: Elexacaftor (VX-445), Tezacaftor (VX-661) and Ivacaftor (VX-770). This therapy, benefits persons with CF, improving their weight, lung function, energy levels (as defined by reduced fatigue), and overall quality of life. We examined the effect of combining LAU-7b oral treatment and Triple therapy combination on lung function in a F508del^tm1EUR mouse model that displays lung abnormalities relevant to human CF. We assessed lung function, lung histopathology, protein oxidation, lipid oxidation, and fatty acid and lipid profiles in F508del^tm1EUR mice.

Keywords: LAU-7b; TRIKAFTA; ceramides; cystic fibrosis; fenretinide (4-HPR); lung physiology; sphingolipids; triple therapy.