Cystic Fibrosis – a Multiorgan Protein Misfolding Disease

Figures & data

Figure 1.  Class I mutations (such as G542X) lead to the premature termination of CFTR protein translation.

Class II mutations include the common F508del (or ΔF508) which lead to the misfolding of CFTR protein and subsequent polyubiquitination and destruction by the cell proteasome. Class III mutations (such as G551D) are also misfolded, but may be transported to the plasma membrane. They are either poorly regulated or nonfunctional and are subsequently degraded by the cell. Class IV mutations lead to a receptor with reduced chloride conductance, whilst class V mutations lead to reduced expression levels of CFTR. Class VI mutations lead to a higher turnover of CFTR at the plasma membrane. Class IV, V and VI mutations lead to a nonclassical or atypical CF phenotype and are not shown.

Table 1.  A list of treatments and medical interventions employed to address cystic fibrosis.

Treatment	Frequency	Target	Purpose
Physiotherapy	Daily^†	Respiratory system	CPT – to help patients expectorate and improve mucocilary clearance of the airways
Enzyme replacement therapy	Regularly	Gastrointestinal tract	Helps overcome some of the problems associated with pancreatic insufficiency
PPIs and antiemetics	As required	Gastrointestinal tract	Often used to help in relieving indigestion and stomach pain and also nausea which might be a side effect of other medications
Antibiotics	As required – regularly	Respiratory system	To reduce microbial infection and colonization of the lung
Osmotic therapy	Daily^†	Respiratory system	Hypertonic saline is usually nebulized as a sterile saline mist. Mannitol, administered as a dry powder, has also been demonstrated to improve lung function
Bronchodilators	Regularly	Respiratory system	B-adrenergic receptor antagonists (both fast acting and long lasting) are commonly used to open the airways in responsive patients and prior to physiotherapy sessions to help patients expectorate. Anticholinergic drugs are less commonly used
Corticosteroids	As required	Respiratory system	Used to ameliorate inflammation in appropriate patients with acute airway inflammation
Nonsteroidal anti-inflammatory drugs	Daily^†	Respiratory system	There is evidence that long-term use of ibuprofen can help to delay deterioration in lung function over time, and the Cystic Fibrosis Foundation recommend its use
Mucolytic agents	Daily^†	Respiratory system	Pulmozyme^®, or donase alfa, is a recombinant human DNAse enzyme marketed by Genentech, and is the leading mucolytic agent used by people with CF. Extracellular DNA (human and microbial) is one of the components of the thick sticky mucous found in CF airways. N-acetylcysteine has also been used as a mucolytic agent for its effects on mucin glycoproteins
Assisted Reproductive Technologies	Rarely	Reproductive system	Can assist men who have bilateral absence of the vas deferens due to mutations on CFTR but no, or mild CF phenotypes.  Assisted reproductive technologies such as IVF have also been used in men and women with more severe phenotypes of CF
Surgery	Once in a lifetime	Respiratory system	Bilateral lung transplants are an option in some patients with severe lung disease. Transplant surgery doesn’t cure CF (as other organs will still be affected) and it does have considerable risks but it can extend the lives of those people with CF who have very poor lung function and may improve the quality of life for some

Patients with the most common severe phenotypes will have experienced many if not most of those listed above during the course of their lives. The Cystic Fibrosis Foundation and other bodies assess the evidence of treatment efficacies gathered through Cochrane reviews and other scientific literature to make informed recommendations for CF patients and their support teams [10].

† Daily treatments for those who require them.

CPT: Chest physiotherapy

Flume PA , O’SullivanBP, RobinsonKAet al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am. J. Respir. Crit. Care Med.176(10), 957–969 (2007).

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