Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?

Cystic fibrosis (CF) is a progressive life–shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leading to a dysfunctional CFTR protein. The disease affects over 70,000 patients worldwide and while many mutations are known, the F508del mutation affects 90% of all patients. The absence of CFTR in the plasma membrane leads to a dramatic decrease in chloride efflux, resulting in viscous mucus that causes severe symptoms in vital organs like the lungs and intestines. For CF patients that suffer from the life threatening F508del mutation only palliative treatment exist. PRO–CF–MED addresses the specific challenge of this call by introducing the first disease modifying medication for the treatment of the CF patients with F508del mutation. The PRO–CF–MED project has been designed to assess the potential clinical efficacy of QR–010, an innovative disease modifying oligonucleotide–based treatment for F508del patients. Partners within PRO–CF–MED have generated very promising preclinical evidence for QR–010 which allows for further clinical assessment of QR–010 in clinical trials. PRO–CF–MED will enable the fast translation of QR–010 towards clinical practice and market authorisation. PRO–CF–MED has the potential to transform this life–threatening condition into a manageable one.

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Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00956-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 5

Author(s):

Melanie Roch ◽

Maria Celeste Varela ◽

Agustina Taglialegna ◽

Warren E. Rose ◽

Adriana E. Rosato

Keyword(s):

Cystic Fibrosis ◽

Staphylococcus Aureus ◽

Galleria Mellonella ◽

Therapeutic Option ◽

The United States ◽

Infection Model ◽

Content Type ◽

Complicated Skin ◽

Hospital Acquired

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90. We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.

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Lung transplantation

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.1816_update_002 ◽

2010 ◽

pp. 3476-3485

Author(s):

P. Hopkins ◽

K. McNeil

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Cystic Fibrosis ◽

Lung Transplantation ◽

Therapeutic Option ◽

Pulmonary Vascular Disease ◽

Chronic Obstructive ◽

Solid Organ ◽

Obstructive Pulmonary Disease ◽

Substance Addiction ◽

Recipient Selection

Lung transplantation offers the only therapeutic option for many patients with a variety of endstage pulmonary and cardiopulmonary diseases, but donors are scarce and the major challenge facing lung transplantation (as with all solid organ transplants) is the critical shortage of donor organs. Recipient selection—emphysema/chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary vascular disease are the main disease groups referred for lung transplantation. Most patients are listed for transplantation when their survival is estimated to be less than 2 years without a transplant. Exclusion criteria include malignancy (excluding localized skin malignancies) within the last 2 years, inability to cooperate or comply with medical therapy/instruction, recent substance addiction, active or noncurable extrapulmonary infection, significant chest wall/spinal deformity, and significant extrathoracic organ dysfunction....

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Rapid Emergence of Resistance to Linezolid and Mutator Phenotypes in Staphylococcus aureus Isolates from an Adult Cystic Fibrosis Patient

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01392-13 ◽

2013 ◽

Vol 57 (10) ◽

pp. 5186-5188 ◽

Cited By ~ 11

Author(s):

Asmaa Tazi ◽

Jeanne Chapron ◽

Gerald Touak ◽

Magalie Longo ◽

Dominique Hubert ◽

...

Keyword(s):

Cystic Fibrosis ◽

Staphylococcus Aureus ◽

Cystic Fibrosis Patient ◽

Therapeutic Option ◽

Clinical Isolates ◽

23S Rrna ◽

Mutator Phenotype ◽

Content Type ◽

Emergence Of Resistance ◽

Rapid Emergence

ABSTRACTLinezolid has emerged as an important therapeutic option for the treatment ofStaphylococcus aureusin patients with cystic fibrosis. We report the rapid emergence, upon treatment with linezolid, of linezolid-resistantS. aureusclinical isolates through the accumulation of resistance-associated 23S rRNA mutations, together with acquisition of an altered mutator phenotype.

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Disease modifying anti-rheumatic drugs in people with cystic fibrosis-related arthritis

Cochrane Database of Systematic Reviews ◽

10.1002/14651858.cd007336.pub3 ◽

2012 ◽

Author(s):

Judith Thornton ◽

Satyapal Rangaraj

Keyword(s):

Cystic Fibrosis ◽

Disease Modifying

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Comparative evaluation of methods testing in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients

10.21203/rs.3.rs-46745/v1 ◽

2020 ◽

Author(s):

Michael Soerensen ◽

Dennis Nurjadi ◽

Bakhodur Khakimov ◽

Sébastien Boutin ◽

Alexander H. Dalpke ◽

...

Keyword(s):

Cystic Fibrosis ◽

Therapeutic Option ◽

Calf Serum ◽

Multidrug Resistant ◽

Term Treatment ◽

In Vitro Sensitivity ◽

Mueller Hinton ◽

Long Term Treatment

Abstract Long-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa . It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment. In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 µg/ml and 12 isolates (41%) showed a MIC ≥512 µg/ml when measured in RPMI/FCS. In contrast, MICs were ≥256 µg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.

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