Elsevier

Paediatric Respiratory Reviews

Volume 25, January 2018, Pages 64-72
Paediatric Respiratory Reviews

Review
Cystic fibrosis in the era of precision medicine

https://doi.org/10.1016/j.prrv.2017.03.001Get rights and content

Summary

The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.

Introduction

Cystic fibrosis (CF), a complex disorder characterized by chronic and progressive pulmonary, pancreatic, gastrointestinal, and hepatobiliary involvement, remains among the most common of life-shortening genetic diseases and affects more than 70,000 individuals worldwide [1], [2]. Cystic fibrosis results from mutations located on chromosome 7q31.2, which encodes a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR) that functions as an apical epithelial chloride channel. To date, over 2000 CFTR mutations have been identified and categorized into six distinct classes that reflect abnormalities of protein synthesis, structure, and function [2], [3], [4] (Figure 1).

Compared to cases described in the sixteenth century [5], median survival in CF has increased steadily, from less than 2 years in 1938 [6], to approximately 30 years in 1989, when the genetic defect was discovered [7], to a median predicted survival age of 41.7 years in 2015 [8]. Improvement in survival has largely resulted from establishment of specialized care centers [9], early disease diagnosis, timely screening for associated comorbidities [10], [11], implementation of therapies to optimize pulmonary function and nutrition [12], [13], and the establishment of clinical care guidelines to standardize symptom based treatments [14], [15].

Currently, the focus of CF therapeutics is shifting from symptom treatment to development of therapies targeting the basic defect in CFTR-mediated chloride transport. Two therapies, ivacaftor and a drug combining lumacaftor and ivacaftor, were approved by the United States Food and Drug Administration (FDA) in 2012 and 2015, respectively [16], [17], for individuals with specific CFTR gene mutations. In keeping with the goals of precision medicine, these drugs personalize treatment based on an individual’s CFTR mutations. While these agents cannot reverse existing disease, they have the potential to alter disease trajectories and improve overall health, quality of life, and survival. Ivacaftor is a potentiator effective in the setting of CFTR mutations producing abnormal CFTR protein at the cell surface. The combination of the corrector lumacaftor, which improves abnormal CFTR trafficking, with ivacaftor is approved in the US for individuals with CF over 6 years of age with two F508del CFTR mutations. Presently, the available personalized therapies have the potential to treat approximately 60% of the CF population.

Section snippets

Precision Medicine

Precision medicine, which incorporates preventive and therapeutic strategies and takes into account differences among individuals [18], has been the focus of initiatives to improve both health and disease through the integration of science, technology, and research. A systems approach, termed “P4 medicine” [19], has been well described in oncology [20], [21], [22] and is directly applicable to a genetic disease such as CF [23], [24]. The P4 model maximizes wellness by treating disease through:

Cystic Fibrosis Presentation

In CF, primary involvement occurs in the respiratory tract, in which mucous plugging, inflammation, and bacterial infection lead to progressive small airways obstruction and bronchiectasis; and the gastrointestinal and hepatobiliary tracts and exocrine pancreas, in which inspissation of viscid secretions leads to intestinal obstruction, cholestasis, and fat and protein malabsorption. Historically, infants and young children present clinically with recurrent respiratory infections, chronic

Diagnosis

The predictive component of P4 medicine directly applies to the process of diagnosing CF, which has not only broadened our knowledge of the complex genetic and phenotypic variability in affected individuals, but also driven the implementation of preventive and personalized therapies. The majority of people with CF in the US are diagnosed by newborn screening, which was pioneered in the 1980s and is carried out worldwide [30]. Newborn screening benefits include early diagnosis, slowing of lung

Cystic Fibrosis Genotype

The current understanding of CFTR genetics and its application to CF diagnosis and treatment is reflected in all four P4 components of precision medicine. As noted previously, CFTR mutations are categorized into six distinct classes that represent alterations of protein synthesis, trafficking, and function [2], [4] (Figure 1). Class I mutations result in no production of CFTR protein because of absent or defective protein biosynthesis. Class II mutations, the best characterized by F508del, lead

Cystic Fibrosis Phenotype

There is great phenotypic variability in CF. Some of the variability, such as that seen with pancreatic functional status, can be explained by the CFTR genotype. Nevertheless, significant individual variability, even among people with the same CFTR mutation, highlights the fundamentals of precision medicine. Extensive searches have been conducted to find genetic modifiers that affect the CF phenotype [43]. Genome wide association studies have identified regions of interest with regard to lung

Cystic Fibrosis Therapeutics

CF lung disease results from abnormal airways secretions leading to chronic obstruction, infection, inflammation and eventually to bronchiectasis and parenchymal destruction. Treatment is aimed to optimize lung function and prevent disease progression and other complications. The overall goals of gastrointestinal disease treatment are to attain age-appropriate growth in childhood and optimize nutritional status. Treatment of pulmonary and gastrointestinal manifestations is lifelong and

Impact of Precision Medicine on Cystic Fibrosis Outcomes

Survival continues to improve for individuals with CF. Treatment goals include: early diagnosis, screening, and treatment of the disease and associated manifestations toward optimizing pulmonary function and nutritional status. Pharmacologic interventions, including newer, mutation-specific therapies, have had a profound effect on overall health and well-being. Effective communication among primary care physicians, subspecialists, and the affected individual and family are paramount to

How can precision medicine continue to have an impact on clinical outcomes in CF?

Understanding disease pathogenesis leads to the development of standardized treatment guidelines, which drives the advancement of new therapies and personalized care regimens. Customizing treatment can be accomplished based on multiple factors (such as genotype, or even individual preference), and in turn further improve outcomes on the basis of utilizing targeted therapies as well as improving adherence. The full impact of new therapies on slowing lung disease progression and preventing the

Conclusion

The principles of precision medicine have already been applied to a better understanding of CF genetics, pathophysiology, and even treatment that targets the defective protein. Identification of new disease causing variants and genetic modifiers have a potential impact on predicting disease progression and individual risk factors for disease-associated processes such as chronic infection, inflammation, and other systemic manifestations. The advancement in knowledge underlying an individual’s

Directions for future research

  • Predictive: Functional characterization of disease causing CFTR mutations

  • Personalized: Identification of genetic modifiers and environmental influences

  • Preventive: Continued development of therapies that correct the basic genetic defect and target disease-specific systemic manifestations

  • Participatory: Design of individual and community driven studies in addition to traditional clinical trials to facilitate therapeutic development

Educational aims

The reader will be able to:

  • 1.

    Describe precision medicine and its role in cystic fibrosis therapeutics and outcomes

  • 2.

    Identify the relationship between cystic fibrosis genotype and phenotype

  • 3.

    Describe the potential for new therapies to address the basic defect in cystic fibrosis on an individualized basis.

Acknowledgements

Dr. Paranjape has received grant funding from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals. Dr. Mogayzel has received grant funding from the Cystic Fibrosis Foundation.

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