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Cystic Fibrosis

Research a Disease of the Human Body:

Cystic Fibrosis

Cystic Fibrosis (CF) is a genetic disease that affects the lungs and digestive system, with epithelial cells producing viscous mucus that inhibits essential system functioning and causes life-threatening infections. A number of drug therapies such as antibacterial agents have become established as effective treatments for the disease, contributing to greatly improved life expectancy and improved morbidity for CF patients. New research into treatment options using drug therapies continues to refine and improve the current treatment regimes. Additionally, new research using gene therapy approaches shows great promise to significantly improve treatment options available and the clinical outcomes for CF patients.

Cystic Fibrosis (CF) is "the most common lethal genetic disorder in Caucasian populations" (Zhang, et al., 2009), disrupting the activity of epithelial cells: "cells that make up the sweat glands in the skin and that also line passageways inside the lungs, liver, pancreas, and digestive and reproductive systems." (Kids Health, n.d.). The gene causes the epithelial cells to produce a defective protein called CFTR (or cystic fibrosis transmembrane conductance regulator) that prevents the epithelial cells from regulating "the way chloride (part of the salt called sodium chloride) passes across cell membranes. This disrupts the essential balance of salt and water needed to maintain a normal thin coating of fluid and mucus inside the lungs, pancreas, and passageways in other organs. The mucus becomes thick, sticky, and hard to move." (Kids Health, n.d.). Without normal mucus transport, the patient is subject to infections. Additionally, mucus in the pancreas "blocks the channels that would normally carry important enzymes to the intestines to digest foods. When this happens, the body can't process or absorb nutrients properly, especially fats." (Kids Health, n.d.). Symptoms of the disease can include:

very salty-tasting skin;

persistent coughing, at times with phlegm;

frequent lung infections;

wheezing or shortness of breath;

poor growth/weight gain in spite of a good appetite; and frequent greasy, bulky stools or difficulty in bowel movements. (Cystic Fibrosis Foundation, n.d.)

Roughly 30,000 U.S. patients are afflicted with the disease, and approximately 1,000 new cases of cystic fibrosis are diagnosed annually. Most patients (more than 70%) are diagnosed by the age of two. During the early and mid-twentieth century, very few children born with cystic fibrosis lived to elementary school age. Today, however, many research advances and new treatments have enhanced and extended the life span and quality of life for children and adults who have CF. Many people with the disease now can now expect to live into the decades of their 30's, 40s and even beyond. Today, more than 45% of CF patients today are age 18 or older, with a median survival age of 37 years. (Cystic Fibrosis Foundation, n.d.)

Researchers continue to develop new therapies and treatments to extend the life span and improve quality of life for Cystic Fibrosis patients, and ease the end-of-life experience. Some of the promising research approaches being explored include drug therapies and gene therapies. Drug therapy approaches include antibacterials, anti-inflammatory agents, and ion channel modeling agents (Jones & Helm, 2009). The majority of CF morbidity and mortality is caused by bacterial infection Pseudomonas aeruginosa (PA). Currently 55 sites nationally are participating in "the Early Pseudomonas Infection Control (EPIC) study, a 300-patient study funded by the National Institutes of Health (NIH)." (Seattle Children's Hospital, 2007). While trials of a potential PA vaccine did not demonstrate efficacy, approaches using various inhaled agents are proving more promising. For example, dry powder versions of tobramyacin (TOBI, which has become a standard CF treatment), and Ciproflaxin (Cipro) are underway (Jones & Helm, 2009). Oral approaches have been found to be effective with use of macrolides, particularly azithromycin, "including reductions in hospitalization, and improvements in lung function and quality of life." (Jones & Helm, 2009).

Another area of pharmacologic treatment is the use of anti-inflammatory agents, to help prevent damage that can be caused by prolonged inflammation of the lung tissues in CF patients. While corticosteroids have been found to be effective at reducing inflammation, they can also have significant adverse side effects, so better anti-inflammatory options have been sought by researchers. Various other approaches have been tried, for example using NSAIDS (like ibuprofin), and inhaled phosphodiesterase-5 inhibitors; while some have shown potential in trials, none have demonstrated clear success, and there are safety concerns attached to many of them. At the moment, oral macrolides continue to be the best option for an anti-inflammatory treatment. Various other drug-based treatments, including the use of mucolytics to break up thick, viscous sputum and the use of osmotic agents to keep airways moist, are well established in CF treatment protocols, but research continues in order to refine and improve on these approaches as well.

A novel therapeutic method being tried for CF is "the modulation of non-CFTR ion channels in epithelial cells." (Jones & Helm, 2009). The drug Lancovutide (Milil901, duramycin) "activates an alternative chloride channel in epithelial cells by elevating intracellular calcium levels, and thus, may potentially compensate for CFTR deficiency in the airway epithelium." (Jones & Helm, 2009). These agents have reached the clinical trial stage, and, if successful, will be able to offer a new category of treatment option for CF patients.

Gene therapies, which seek to correct "the underlying gene effect, either by agents that help to correct the dysfunctional CFTR . . . Or by gene transfer" (Jones & Helm, 2009), are particularly promising. The gene defect that causes CF was first identified in 1989, and since then researchers have explored treatments that would replace the patient's defective CFTR with "wild-type" CFTR (Jones & Helm, 2009).

For example Zhang, et al. have focused on the development of gene transfer strategies using epithelial cells. They used "an in vitro model of human CF ciliated surface airway epithelium…to test whether a human parainfluenza virus vector engineered to express CFTR could deliver sufficient CFTR…to restore mucus transport, thus correcting the CF phenotype." (Zhang, et al., 2008). The team was able to determine that normal mucus transport rates were restored after "CFTR delivery to 25% of surface epithelial cells." (Zhang, et al., 2008). Additional study will help develop this corrective gene transfer approach and determine how best to use the technique and how far it can go towards restoring normal mucus transport function in CF patients.