CORK Study in Cystic Fibrosis

Ronan, N.J.; Einarsson, G.G.; Twomey, Maria; Mooney, D.; Mullane, D.; NíChróinín, Muireann; O'Callaghan, G.; Shanahan, Fergus; Murphy, Desmond M.; O’Connor, Owen J.; Shortt, C.; Tunney, Michael; Eustace, Joseph A.; Maher, Michael M.; Elborn, J.S.; Plant, Barry J.

doi:10.1016/j.chest.2017.10.005

Cited by 78 publications

(38 citation statements)

References 41 publications

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“…Furthermore, observational studies have demonstrated that ivacaftor improved pancreatic function and mucociliary clearance. Reduction in the levels of blood inflammatory biomarkers, and smooth muscle and lung structure abnormalities have also been observed (Adam et al, 2016;Hisert et al, 2017;Donaldson et al, 2018b;Ronan et al, 2018).…”

Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 92%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 92%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…Here, we explore the complex role of streptococci in CF-associated airway infections ( Fig. 1), in particular, the observation that streptococci, in a species-dependent fashion, either may be associated with a lower disease burden than typical CF pathogens (2,9,12,21,29) or, alternatively, may contribute to pulmonary exacerbations (1,6,(17)(18)(19). We also review recent studies indicating that streptococci influence and can be influenced by other microbes in the context of a polymicrobial infection in patients with CF.…”

Section: )mentioning

confidence: 99%

“…The interaction of P. aeruginosa with S. pneumoniae has not been investigated in any In CF airways, an increased prevalence of Streptococcus spp. has been correlated with clinical stability, lower inflammation, and/or less severe outcomes (2,9,12,21,29), but it is unclear whether this is due to direct interactions with the airway epithelium, is due to interactions between the streptococci and the microbiome that lead to increased microbial diversity, or is a consequence of less damage to the airway. Oral streptococci have been demonstrated to inhibit P. aeruginosa growth through the production of hydrogen peroxide and reactive nitrogenous intermediates (49)(50)(51); by inhibiting P. aeruginosa, streptococci could open up niches for increased microbial diversity in the lung, which could aid clinical stability.…”

Section: Is There a Role For Typical Pathogenic Streptococci In Cf?mentioning

confidence: 99%

“…Five recent microbiome studies indicate that colonization of the CF lung by oral Streptococcus spp. may be associated with a disease burden less severe than that associated with typical CF pathogens (2,9,12,21,29). Work from our group has indicated that an increased relative abundance of members of the genus Streptococcus in the lung, determined by 16S rRNA gene sequencing, correlates with clinical stability (2).…”

Section: Streptococci Are Associated With Disease Less Severe Than Thmentioning

confidence: 99%

“…Another study utilizing 16S rRNA gene sequencing indicated that the relative abundance of streptococci was significantly lower in patients with CF in the lowest quartile of forced expiratory volume in 1 s (FEV 1 ), a key marker of lung function (9); thus, a low relative abundance of streptococci (and, thus, a higher abundance of other CF pathogens) was associated with poorer lung function. It has also been demonstrated that the relative abundance of streptococci increases when patients undergo CF transmembrane conductance regulator modulation therapy with ivacaftor, while the relative abundance of P. aeruginosa declines (12). In another study, Acosta et al, studying a cohort of 104 patients with CF (18 to 22 years of age), showed that higher levels of Streptococcus were associated with a decreased likelihood of progressing to early end-stage lung disease (29).…”

Section: Streptococci Are Associated With Disease Less Severe Than Thmentioning

confidence: 99%

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The Yin and Yang of Streptococcus Lung Infections in Cystic Fibrosis: a Model for Studying Polymicrobial Interactions

Scott

O’Toole

2019

J Bacteriol

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The streptococci are increasingly recognized as a core component of the cystic fibrosis (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The presence of the Streptococcus milleri group (SMG; also known as the anginosus group streptococci [AGS]) correlates with exacerbation when these microbes are the predominant species in the lung. In contrast, microbiome studies have indicated that an increased relative abundance of streptococci in the lung, including members of the oral microflora, correlates with impacts on lung disease less severe than those caused by other CF-associated microflora, indicating a complex role for this genus in the context of CF. Recent findings suggest that streptococci in the CF lung microenvironment may influence the growth and/or virulence of other CF pathogens, as evidenced by increased virulence factor production by Pseudomonas aeruginosa when grown in coculture with oral streptococci. Conversely, the presence of P. aeruginosa can enhance the growth of streptococci, including members of the SMG, a phenomenon that could be exacerbated by the fact that streptococci are not susceptible to some of the frontline antibiotics used to treat P. aeruginosa infections. Collectively, these studies indicate the necessity for further investigation into the role of streptococci in the CF airway to determine how these microbes, alone or via interactions with other CF-associated pathogens, might influence CF lung disease, for better or for worse. We also propose that the interactions of streptococci with other CF pathogens is an ideal model to study clinically relevant microbial interactions.

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Rapid therapeutic advances in CFTR modulator science

Clancy

2018

Pediatric Pulmonology

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Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding the cystic fibrosis transmembrane conduction regulator (CFTR) protein. Loss of CFTR function disrupts chloride, bicarbonate and regulation of sodium transport, producing a cascade of mucus obstruction, inflammation, pulmonary infection, and ultimately damage in numerous organs. Established CF therapies treat the downstream consequences of CFTR dysfunction and have led to steady improvements in patient survival. A class of drugs termed CFTR modulators has recently entered the CF therapeutic landscape. These drugs differ fundamentally from prior therapies in that they aim to improve the function of disease‐causing CFTR variants. This review summarizes the science behind CFTR modulators, including their targets, mechanism of action, clinical benefit, and future directions in the field. CFTR modulators have dramatically changed how CF is treated, validated CFTR as a therapeutic target, and opened the door to truly personalized therapies and treatment regimens.

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CORK Study in Cystic Fibrosis

Abstract: Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

Cited by 78 publications

References 41 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

The Yin and Yang of Streptococcus Lung Infections in Cystic Fibrosis: a Model for Studying Polymicrobial Interactions

Rapid therapeutic advances in CFTR modulator science

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