Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine

Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over the last few years, new technologies have been developed, and gene editing strategies are now moving toward a one-time cure. This review will summarize recent advances in etiological therapies that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve its function. Moreover, we will discuss how proteostasis regulators can modify the environment in which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.

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Systems Biology and Bile Acid Signalling in Microbiome-Host Interactions in the Cystic Fibrosis Lung

Antibiotics ◽

10.3390/antibiotics10070766 ◽

2021 ◽

Vol 10 (7) ◽

pp. 766

Author(s):

David F. Woods ◽

Stephanie Flynn ◽

Jose A. Caparrós-Martín ◽

Stephen M. Stick ◽

F. Jerry Reen ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bile Acids ◽

Host Response ◽

Signal Molecules ◽

Therapeutic Approaches ◽

Related Factors ◽

Host Interactions ◽

Important Host ◽

Respiratory Microbiota

The study of the respiratory microbiota has revealed that the lungs of healthy and diseased individuals harbour distinct microbial communities. Imbalances in these communities can contribute to the pathogenesis of lung disease. How these imbalances occur and establish is largely unknown. This review is focused on the genetically inherited condition of Cystic Fibrosis (CF). Understanding the microbial and host-related factors that govern the establishment of chronic CF lung inflammation and pathogen colonisation is essential. Specifically, dissecting the interplay in the inflammation–pathogen–host axis. Bile acids are important host derived and microbially modified signal molecules that have been detected in CF lungs. These bile acids are associated with inflammation and restructuring of the lung microbiota linked to chronicity. This community remodelling involves a switch in the lung microbiota from a high biodiversity/low pathogen state to a low biodiversity/pathogen-dominated state. Bile acids are particularly associated with the dominance of Proteobacterial pathogens. The ability of bile acids to impact directly on both the lung microbiota and the host response offers a unifying principle underpinning the pathogenesis of CF. The modulating role of bile acids in lung microbiota dysbiosis and inflammation could offer new potential targets for designing innovative therapeutic approaches for respiratory disease.

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Personalized medicine for cystic fibrosis: Establishing human model systems

Pediatric Pulmonology ◽

10.1002/ppul.23233 ◽

2015 ◽

Vol 50 (S40) ◽

pp. S14-S23 ◽

Cited By ~ 18

Author(s):

Hongmei Mou ◽

Karissa Brazauskas ◽

Jayaraj Rajagopal

Keyword(s):

Cystic Fibrosis ◽

Personalized Medicine ◽

Model Systems ◽

Human Model

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Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽

10.1183/20734735.0112-2021 ◽

2021 ◽

Vol 17 (4) ◽

pp. 210112

Author(s):

Daniel H. Tewkesbury ◽

Rebecca C. Robey ◽

Peter J. Barry

Keyword(s):

Cystic Fibrosis ◽

Precision Medicine ◽

Real World ◽

Chloride Ion ◽

Transmembrane Conductance Regulator ◽

Therapeutic Approaches ◽

Transmembrane Conductance ◽

Cftr Protein ◽

Cystic Fibrosis Transmembrane ◽

Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

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A new Era of Personalized Medicine for Cystic Fibrosis – at Last!

Canadian Respiratory Journal ◽

10.1155/2015/921712 ◽

2015 ◽

Vol 22 (5) ◽

pp. 257-260 ◽

Cited By ~ 3

Author(s):

Bradley S Quon ◽

Pearce G Wilcox

Keyword(s):

Cystic Fibrosis ◽

Personalized Medicine ◽

Late Phase ◽

Structure And Function ◽

Clinical Development ◽

New Era ◽

High Throughput Drug Screening ◽

Cftr Protein ◽

And Function ◽

Screening Approaches

The gene responsible for cystic fibrosis (CF) was discovered 25 years ago. This breakthrough has enabled a sophisticated understanding of how various mutations lead to specific alterations in the structure and function of the CF transmembrane regulator (CFTR) protein. Until recently, all therapies in CF were focused on ameliorating the downstream consequences of CFTR dysfunction. High-throughput drug screening approaches have yielded compounds that can modify CFTR structure and function, thus targeting the basic defect in CF. The present article describes theCFTRmutational classes, reviews mutation-specific therapies currently in late-phase clinical development, and highlights research opportunities and challenges with personalized medicine in CF.

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Delivering on the promise of gene editing for cystic fibrosis

Genes & Diseases ◽

10.1016/j.gendis.2018.11.005 ◽

2019 ◽

Vol 6 (2) ◽

pp. 97-108 ◽

Cited By ~ 7

Author(s):

Craig A. Hodges ◽

Ronald A. Conlon

Keyword(s):

Cystic Fibrosis ◽

Gene Editing

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Editorial: Special Issue on “Therapeutic Approaches for Cystic Fibrosis”

International Journal of Molecular Sciences ◽

10.3390/ijms21186657 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6657

Author(s):

Nicoletta Pedemonte

Keyword(s):

Cystic Fibrosis ◽

Genetic Disease ◽

Special Issue ◽

Therapeutic Approaches ◽

Editorial Special Issue

Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasian populations, occurring in approximately 1 in 3000 newborns worldwide [...]

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The CFTR variant profile of Hispanic patients with cystic fibrosis: Impact on access to effective screening, diagnosis, and personalized medicine

Journal of Genetic Counseling ◽

10.1002/jgc4.1271 ◽

2020 ◽

Vol 29 (4) ◽

pp. 607-615

Author(s):

Megan N. Januska ◽

Laura Marx ◽

Patricia A. Walker ◽

Maria N. Berdella ◽

Elinor Langfelder‐Schwind

Keyword(s):

Cystic Fibrosis ◽

Personalized Medicine ◽

Effective Screening ◽

Hispanic Patients ◽

And Personalized Medicine

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Rehydration of cystic fibrosis airway surfaces: rationale and new therapeutic approaches

Current & Emerging Pharmaceutical Treatments for Cystic Fibrosis Lung Disease ◽

10.2217/ebo.12.523 ◽

2013 ◽

pp. 42-54

Author(s):

Richard C Boucher

Keyword(s):

Cystic Fibrosis ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Cystic Fibrosis Airway

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Milestones in Personalized Medicine: From the Ancient Time to Nowadays—the Provocation of COVID-19

Frontiers in Genetics ◽

10.3389/fgene.2020.569175 ◽

2020 ◽

Vol 11 ◽

Author(s):

Sophie Visvikis-Siest ◽

Danai Theodoridou ◽

Maria-Spyridoula Kontoe ◽

Satish Kumar ◽

Michael Marschler

Keyword(s):

Clinical Practice ◽

Personalized Medicine ◽

Genetic Background ◽

Scientific Field ◽

Diagnostic Tools ◽

Global Awareness ◽

Therapeutic Approaches ◽

Current Crisis ◽

Ancient Times ◽

Over Time

The first evidence of individual targeting medicine appeared in ancient times thousands of years ago. Various therapeutic approaches have been established since then. However, even nowadays, conventional therapies do not take into consideration individuals' idiosyncrasy and genetic make-up, failing thus to be effective in some cases. Over time, the necessity of a more precise and effective treatment resulted in the development of a scientific field currently known as “personalized medicine.” The numerous technological breakthroughs in this field have acknowledged personalized medicine as the next generation of diagnosis and treatment. Although personalized medicine has attracted a lot of attention the last years, there are still several obstacles hindering its application in clinical practice. These limitations have come to light recently, due to the COVID-19 pandemic. This review describes the “journey” of personalized medicine over time, emphasizing on important milestones achieved through time. Starting from the treatment of malaria, as a first more personalized therapeutic approach, it highlights the need of new diagnostic tools and therapeutic regimens based on individuals' genetic background. Furthermore, it aims at raising global awareness regarding the current limitations and the necessity of a personalized strategy to overpass healthcare problems and hence, the current crisis.

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