Ataluren/ivacaftor combination therapy: Two N‐of‐1 trials in cystic fibrosis patients with nonsense mutations

2020 ◽  
Vol 55 (7) ◽  
pp. 1838-1842 ◽  
Author(s):  
Jacelyn E. Peabody Lever ◽  
Venkateshwar Mutyam ◽  
Heather Y. Hathorne ◽  
Ning Peng ◽  
Jyoti Sharma ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Combination Therapy ◽  
Nonsense Mutations

Disruption of biofilms and killing of Burkholderia cenocepacia from cystic fibrosis lung using an antioxidant-antibiotic combination therapy

2021 ◽  
pp. 106372
Author(s):  
Aditi Aiyer ◽  
Arthika Manoharan ◽  
Denis Paino ◽  
Jessica Farrell ◽  
Gregory S. Whiteley ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Combination Therapy ◽  
Burkholderia Cenocepacia ◽  
Cystic Fibrosis Lung ◽  
Antibiotic Combination

scholarly journals Prevalence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis

2019 ◽  
Author(s):  
Laura J. Sherrard ◽  
Bryan A. Wee ◽  
Christine Duplancic ◽  
Kay A. Ramsay ◽  
Keyur A. Dave ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Hazard Rate ◽  
Carbapenem Resistance ◽  
Adverse Outcomes ◽  
Nonsense Mutations ◽  
Allelic Variants ◽  
Novel Variants

ABSTRACTDefective OprD porins contribute to carbapenem resistance and may be important in Pseudomonas aeruginosa adaptation to cystic fibrosis airways. It is unclear whether oprD mutations are fixed in populations of shared strains that are transmitted between patients or whether novel variants arise during infection. We investigated oprD sequences and antimicrobial resistance of two common Australian shared strains, constructed P. aeruginosa mutants with the most common oprD allelic variants and compared characteristics between patients with or without evidence of infection with strains harbouring these variants. Our data show that three independently acquired nonsense mutations arising from a 1-base pair substitution are fixed in strain sub-lineages. These nonsense mutations are likely to contribute to reduced carbapenem susceptibility in the sub-lineages without compromising in vitro fitness. Not only was lung function worse among patients infected with strains harbouring the nonsense mutations than those without, but they also had an increased hazard rate of lung transplantation/death. Our findings further highlight that understanding adaptive changes may help to distinguish patients with greater adverse outcomes despite infection with the same strain.

scholarly journals Therapy for Cystic Fibrosis Caused by Nonsense Mutations

10.5772/61053 ◽  
2015 ◽  
Author(s):  
Roberto Gambari ◽  
Giulia Breveglieri ◽  
Francesca Salvatori ◽  
Alessia Finotti ◽  
Monica Borgatti
Keyword(s):  
Cystic Fibrosis ◽  
Nonsense Mutations

Efficacy of inhaled amikacin as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis

1987 ◽  
Vol 111 (4) ◽  
pp. 599-605 ◽  
Author(s):  
Urs B. Schaad ◽  
Joanna Wedgwood-Krucko ◽  
Susanne Suter ◽  
Richard Kraemer
Keyword(s):  
Cystic Fibrosis ◽  
Combination Therapy ◽  
Inhaled Amikacin

scholarly journals Two Patients with Cystic Fibrosis, Nonsense Mutations in Each Cystic Fibrosis Gene, and Mild Pulmonary Disease

1990 ◽  
Vol 323 (24) ◽  
pp. 1685-1689 ◽  
Author(s):  
Garry R. Cutting ◽  
Laura M. Kasch ◽  
Beryl J. Rosenstein ◽  
Lap-Chee Tsui ◽  
Haig H. Kazazian ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pulmonary Disease ◽  
Cystic Fibrosis Gene ◽  
Nonsense Mutations

New Pharmacological Approaches to Treat Patients with Cystic Fibrosis with Nonsense Mutations

2016 ◽  
Vol 194 (9) ◽  
pp. 1042-1044 ◽  
Author(s):  
Isabelle Sermet-Gaudelus ◽  
Olivier Namy
Keyword(s):  
Cystic Fibrosis ◽  
Nonsense Mutations

scholarly journals Efficient Suppression of Endogenous CFTR Nonsense Mutations Using Anticodon Engineered Transfer RNAs

2021 ◽  
Author(s):  
Wooree Ko ◽  
Joseph J. Porter ◽  
Matthew T. Sipple ◽  
Katherine M. Edwards ◽  
John D. Lueck
Keyword(s):  
Cystic Fibrosis ◽  
Mammalian Cells ◽  
Genetic Diseases ◽  
Protein Translation ◽  
Nonsense Mutations ◽  
Channel Function ◽  
Associated Diseases ◽  
Highly Active ◽  
Premature Termination Codons ◽  
Efficient Suppression

Nonsense mutations or premature termination codons (PTCs) comprise ~11% of all genetic lesions, which result in over 7,000 distinct genetic diseases. Due to their outsized impact on human health, considerable effort has been made to find therapies for nonsense-associated diseases. Suppressor tRNAs have long been identified as a possible therapeutic for nonsense-associated diseases, however their ability to inhibit nonsense-mediated mRNA decay (NMD) and support significant protein translation from endogenous transcripts has not been determined in mammalian cells. Here we investigated the ability of anticodon edited (ACE)-tRNAs to suppress cystic fibrosis (CF) causing PTCs in the cystic fibrosis transmembrane regulator (CFTR) gene in gene-edited immortalized human bronchial epithelial (16HBEge) cells. Delivery of ACE-tRNAs to 16HBEge cells harboring three common CF mutations G542X-, R1162X- and W1282X-CFTR PTCs significantly inhibited NMD and rescued endogenous mRNA expression. Furthermore, delivery of our highly active leucine encoding ACE-tRNA resulted in rescue of W1282X-CFTR channel function to levels that significantly exceed the necessary CFTR channel function for therapeutic relevance. This study establishes the ACE-tRNA approach as a potential stand-alone therapeutic for nonsense-associated diseases due to its ability to rescue both mRNA and full-length protein expression from PTC containing endogenous genes.

scholarly journals Virulence attenuating combination therapy: a potential multi-target synergy approach to treat Pseudomonas aeruginosa infections in cystic fibrosis patients

2020 ◽  
Vol 11 (3) ◽  
pp. 358-369 ◽  
Author(s):  
Elana Shaw ◽  
William M. Wuest
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Combination Therapy

Virulence attenuating combination therapy may be a promising approach to treating chronic P. aeruginosa infections in patients with cystic fibrosis.

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