Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Haq, Iram; Almulhem, Maryam; Soars, Simone; Poulton, David W.; Brodlie, Malcolm

doi:10.2147/pgpm.s245603

Cited by 15 publications

(19 citation statements)

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“…Class VI mutations result in a decreased CFTR stability at the level of the apical membrane due to higher endocytosis rates or lower plasmatic membrane recycling ones [ 4 , 6 , 8 , 87 ].…”

Section: Pert and Cftr Modulator Therapiesmentioning

confidence: 99%

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

et al. 2023

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This review presents current updates of pancreatic enzyme replacement therapy in children with cystic fibrosis based on literature published in the last decade and some special considerations regarding pancreatic enzyme replacement therapy in the era of new therapies, such as cystic fibrosis transmembrane conductance regulator modulator therapies. Few articles evaluate the efficacy of pancreatic enzyme replacement therapy in the pediatric population, and most studies also included children and adults with cystic fibrosis. Approximately 85% of cystic fibrosis patients have exocrine pancreatic insufficiency and need pancreatic enzyme replacement therapy. Fecal elastase is the most commonly used diagnostic test for exocrine pancreatic insufficiency, although this value can fluctuate over time. While it is used as a diagnostic test, it cannot be used for monitoring the effectiveness of pancreatic enzyme replacement therapy and for adjusting doses. Pancreatic enzyme replacement therapy, the actual treatment for exocrine pancreatic insufficiency, is essential in children with cystic fibrosis to prevent malabsorption and malnutrition and needs to be urgently initiated. This therapy presents many considerations for physicians, patients, and their families, including types and timing of administration, dose monitoring, and therapy failures. Based on clinical trials, pancreatic enzyme replacement therapy is considered effective and well-tolerated in children with cystic fibrosis. An important key point in cystic fibrosis treatment is the recent hypothesis that cystic fibrosis transmembrane conductance regulator modulators could improve pancreatic function, further studies being essential. Pancreatic enzyme replacement therapy is addressed a complication of the disease (exocrine pancreatic insufficiency), while modulators target the defective cystic fibrosis transmembrane conductance regulator protein. Exocrine pancreatic insufficiency in cystic fibrosis remains an active area of research in this era of cystic fibrosis transmembrane conductance regulator modulator therapies. This new therapy could represent an example of personalized medicine in cystic fibrosis patients, with each class of modulators being addressed to patients with specific genetic mutations.

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“…Class VI mutations result in a decreased CFTR stability at the level of the apical membrane due to higher endocytosis rates or lower plasmatic membrane recycling ones [ 4 , 6 , 8 , 87 ].…”

Section: Pert and Cftr Modulator Therapiesmentioning

confidence: 99%

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

et al. 2023

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“…These small molecule drugs target the underlying defect and improve CFTR function. 7 Depending on the functional class of CFTR variant either a potentiator or combination of potentiator and correctors are prescribed. Potentiators increase the amount of time that the CFTR channel is open and improve gating defects.…”

Section: Introductionmentioning

confidence: 99%

“…Correctors improve the trafficking of CFTR to the cell membrane when there is a problem with misfolding of the protein causing it to be degraded intracellularly. 7 Over 80% of cwCF in the UK have at least one copy of the F508del variant where a combination of correctors and potentiator is used to firstly transport the F508del CFTR protein to the membrane and then increase the amount of time the channel is open. 8 In this population the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI), Kaftrio , has been demonstrated to substantially improve lung function, increase time to next pulmonary exacerbation and improve weight and quality of life in well-conducted randomised trials.…”

Section: Introductionmentioning

confidence: 99%

“…The development of CFTR modulators has heralded a new era of precision medicine in CF. These small molecule drugs target the underlying defect and improve CFTR function 7. Depending on the functional class of CFTR variant either a potentiator or combination of potentiator and correctors are prescribed.…”

Section: Introductionmentioning

confidence: 99%

“…Potentiators increase the amount of time that the CFTR channel is open and improve gating defects. Correctors improve the trafficking of CFTR to the cell membrane when there is a problem with misfolding of the protein causing it to be degraded intracellularly 7. Over 80% of cwCF in the UK have at least one copy of the F508del variant where a combination of correctors and potentiator is used to firstly transport the F508del CFTR protein to the membrane and then increase the amount of time the channel is open 8.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the impact of elexacaftor-tezacaftor-ivacaftor treatment on opinions regarding airway clearance techniques and nebulisers: TEMPO a qualitative study in children with cystic fibrosis, their families and healthcare professionals

et al. 2022

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BackgroundCystic fibrosis (CF) is a genetic condition caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that primarily impacts the lungs. Treatments historically have been symptomatic to improve airway clearance and treat infection. However, CFTR modulator drugs have recently been developed that target the underlying defect. The triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2020 in England for over 80% of people with CF aged over 12 years and in 2022 extended to those over 6 years. ETI treatment is associated with substantial improvements in lung function. The experience of children with CF starting on ETI or their views regarding future treatments have not been well studied. This study aimed to explore the opinions of children with CF, their parents/carers and healthcare professionals (HCPs) on the impact of ETI, airway clearance techniques (ACTs) and nebulised treatments.MethodsSemistructured qualitative interviews were performed with 10 children with CF, 7 parents/carers and 10 HCPs. Audio recordings were transcribed and analysed using reflexive thematic analysis.ResultsFour main themes were identified: ‘Kaftrio changed my life’, ‘Your entire life is dictated by the CF timetable’, ‘Simplifying treatment-hopes and fears’ and ‘Kaftrio is a game-changer’ along with several subthemes and an overarching theme of ‘I still can’t get my head around how three tablets can do what Kaftrio done’.ConclusionsDespite the highly positive impact of ETI on the health of children with CF some concerns remain about the longer-term outcomes of reducing ACTs or nebulised treatments. ETI has prompted a shift in treatment for many and offers an opportunity to personalise approaches.

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Mathematical models of cystic fibrosis as a systemic disease

Olivença

Davis

Kumbale

et al. 2023

WIREs Mechanisms of Disease

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Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi‐species bacterial communities, called “infection microbiomes,” that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi‐scale modeling framework, known as template‐and‐anchor modeling, that allows the gradual integration of refined sub‐models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases.This article is categorized under: Congenital Diseases > Computational Models

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Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Cited by 15 publications

References 96 publications

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

Exploring the impact of elexacaftor-tezacaftor-ivacaftor treatment on opinions regarding airway clearance techniques and nebulisers: TEMPO a qualitative study in children with cystic fibrosis, their families and healthcare professionals

Mathematical models of cystic fibrosis as a systemic disease

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