Cystic Fibrosis

By Ellen Klenk

I. INTRODUCTION

Cystic fibrosis (CF) is the most common genetic disease in the United States. About one out of every 3300 babies born in the United States has CF, and one out of every twenty people is a carrier for the disease (Cystic Fibrosis Foundation, 1999). CF is a homozygous recessive disorder caused by a mutation in a single gene called Cystic Fibrosis Transmembrane Regulator, or simply CFTR. There are over 400 different mutations that are known to cause CF, but only about twenty occur commonly (NHLBI, 1999). The average life span for an individual with CF born today is 27 years (Laag, 1995). The extreme prevalence and devastating nature of cystic fibrosis make it a serious health concern and a major area of research. CF is particularly important to me not because of its prevalence, but more importantly because the disease has struck my family.
There are several different clinical problems seen in CF patients that are caused by mutations in the CFTR gene. Although the severity of CF can vary from person to person, there are several clinical features present in almost everyone affected: lung disease, digestive problems, sterility, and abnormal sweat glands (Cystic Fibrosis, 1999).

Lung disease is the most serious complication seen with cystic fibrosis. The epithelial cells in the lungs of patients with CF secrete a very thick mucus because of the mutation to the CFTR protein (Laag, 1995). This mucus is nearly impossible for patients to clear from their lungs, so it serves as a breeding ground for bacteria and results in chronic lung infections. Most patient’s airways are colonized with bacteria early in life, and once colonization begins, it is nearly impossible to rid the lungs of the bacteria since they tend to gain resistance to multiple antibiotics. The chronic lung infections gradually cause lung function to deteriorate, and eventually the lungs are unable to supply enough oxygen to the person for him or her to survive (Laag, 1995).

A second major clinical problem seen in cystic fibrosis patients is digestive insufficiency. Cells lining the ducts that normally carry enzymes from the pancreas to the intestines produce the same abnormally thick mucus as that in the lungs of CF patients, and it prevents enzymes from reaching the small intestine (Cystic Fibrosis Foundation, 1999). These enzymes are vital for proper digestion, so individuals suffering from pancreatic insufficiency must take artificial enzymes orally to be able to digest their food properly (Marshall and Samuelson, 1998). In the past, many CF patients died because of improper digestion, but today, improved means of nutritional support have all but eradicated digestive problems as a life threatening problem for individuals with CF (Buchwald, 1996).

The large majority of males and many females who have cystic fibrosis also suffer from infertility. Males with CF are usually born with atrophy or absence of the vas deference, epididimus, and seminal vesicles making them completely sterile. Women, however, generally suffer from reduced fertility rather than complete sterility. Although the exact cause of decreased fertility is not well characterized, it is thought to be caused by excess secretion of cervical mucus (Buchwald, 1996).

A less serious clinical feature of cystic fibrosis is that CF patients have sweat glands which are unable to reabsorb salt properly, so CF patients lose excessive amounts of salt in their sweat (Cystic Fibrosis, 1999). The high concentration of salt in the sweat is the basis for the most common test for cystic fibrosis which involves stimulating the production of sweat by placing the chemical pilocarpine on the skin and applying a mild electrical current. The test is painless, quick, and very accurate making it the most common method of screening for cystic fibrosis (Rosenstein and Zeitlin, 1998).

II HISTORY

Cystic fibrosis was first characterized by the Swiss doctor Fanconi. He described CF as "coeliac syndrome with pancreatic changes," but he did not recognize any of the respiratory symptoms associated with the disease (Super 1992). For the next two decades, the cause of CF was unknown, but some individuals hypothesized that it was caused by a vitamin deficiency. It was not until 1952 that cystic fibrosis was accepted by the majority of researchers and doctors to be a genetic disease (Super 1992).

Through the next forty years, there were many advances in CF research. Researchers developed new treatments for the disorder and came to a clear understanding of the problems faced by individuals with cystic fibrosis. The most exciting breakthrough in CF research occurred in 1989 when Collins, Tsui, and Riordan discovered the gene responsible for causing cystic fibrosis, Cystic Fibrosis Transmembrane Regulator (CFTR) (Super, 1992). They sequenced the gene and realized that a deletion of three base pairs coding for phenylalanine causes CF. Following this discovery, more than 400 other mutations were found that can cause CF (Super, 1992).

III. GENETICS

Cystic fibrosis is caused by one or more mutations to the gene CFTR that codes for a protein with the same name, and it is expressed in the epithelial cells of the lungs, pancreas, genitourinary tract, colon, and sweat glands (Buchwald, 1992). CFTR is an integral transmembrane protein, and it functions as a chloride ion channel providing a passage in the cell membrane through which chloride ions can pass (Sheppard and Welsh, 1992). Normally, the channel is used to move negatively charged chloride ions out of the cell. This movement induces positively charged sodium ions to follow, and because water tends to follow salts, water leaves the cell as well (NHLBI 1999). In individuals with cystic fibrosis, a mutation in the CFTR gene causes the protein to be defective (Cystic Fibrosis, 1999). Currently, most researchers agree that the defect in the protein is that it is missing glycoproteins on its surface that would normally identify it as a membrane protein. Therefore, CFTR is never brought to the surface of the cell. Recent studies indicate that the CFTR would be fully functional if it were allowed to reach the cell membrane, but it is targeted for degradation before it does so (Ko and Pedersen, 1997). Since CFTR never reaches the epithelial cell membranes in people with cystic fibrosis, it is unable to function as a chloride ion channel. The chloride and sodium ions are retained in the cell and, because of the salt retention, water is retained as well (Sheppard and Welsh, 1999). The result is that the cells produce very thick mucus since it does not contain enough water.

CFTR consists of a single chain of 1480 amino acids divided into 5 major domains (Ko, and Pedersen, 1997). The more than 400 mutations that can lead to cystic fibrosis are found throughout these domains (NHLBI, 1999). The most common mutation resulting in CF, deltaF508, is found in one domain consisting of intracellular binding folds. DeltaF508 accounts for 80-90% of all cases of CF, and unfortunately, it results in a severe form of the disease (Ko and Pedersen, 1997). Currently, there is little information on the specific three-dimensional shape of CFTR, so it is unknown exactly how this mutation changes the shape of the protein (Ko and Pedersen, 1997).

IV. TREATMENT

A. Treatments to Improve Lung Function

Because there is currently no cure for cystic fibrosis, the approach most physicians take in managing CF is to treat the symptoms. The primary goals of CF therapy are to improve nutritional status, slow the progression of pulmonary disease, and to improve quality of life (Rosenstein, and Zeitlin, 1998). Because CF causes problems in so many different body systems, many different kinds of treatment are utilized for each CF patient.

Antibiotics have been used to treat CF for more than forty years. The thick mucus that accumulates in the lungs of CF patients serves as a breading ground for bacteria. One kind of bacteria, P. aeruginosa tends to cause the most problems for individuals with cystic fibrosis because after colonization has occurred, the bacteria are difficult, if not impossible, to eradicate (Rosenstein and Zeitlin., 1998). Antibiotic agents are not just used to treat ongoing infections, but they are also used to prophylactically to slow the progression of lung damage. This form of therapy is called maintenance therapy, but it is actually just a modified form of antibiotic treatment. Tobramycin is the most commonly used antibiotic for maintenance therapy (Marshall and Samuelson. 1998).

A second form of CF treatment that is intended to help improve lung function and to decrease the number of bacteria in the lungs is airway clearance therapy or ACT. The most commonly used form of ACT has traditionally been postural drainage, percussion, and vibration (Simakajornboon and Davis, 1998). In this conventional form of ACT, the patient lays in various positions while another individual claps on their chest with their hands or a vibrating device (NHLBI, 1999). This percussion loosens the thick mucus secretions and facilitates their movement into the central airway where they can be removed by coughing (Simakajornboon and Davis, 1998). This technique is extremely beneficial for maintaining lung health. A less traditional form of airway clearance therapy is exercise. Physicians have recently begun recommending physical activity as a way to stimulate airway clearance. Good physical fitness tends to improve lung function in CF patients and helps loosen the mucus blocking the lungs, mimicking traditional forms of ACT (Marshall and Samuelson, 1998).

A relatively new form of treatment for cystic fibrosis is mucolytic therapy. A mucolytic is a substance that decreases the viscosity of CF sputum (NHLBI ,1999). One of the reasons that the sputum of CF patients is unusually thick is because it contains large quantities of extracellular DNA that is released by white blood cells into the airways (Simakajornboon, and Davis 1998). Investigators hypothesized that breaking this DNA into smaller particles would help to reduce the viscosity of the mucus. Researchers found recombinant human DNase, an enzyme that degrades DNA, significantly decreased the viscosity of the secretions. This mucolytic has been available commercially since 1994, and it has been shown to be very effective for treating CF (Marshall and Samuelson, 1998).

CF patients suffer from chronic bacterial lung infections that cause severe airway inflammation. Recently, investigators have come to the conclusion that anti-inflammatory agents would be useful for treating CF patients, and both steroid and non-steroid anti-inflammatory drugs have been investigated for their abilities to improve lung function. One study evaluated the effectiveness of prednisone for improving lung health in CF patients. This investigation found that the patients who received the prednisone had more growth, a lower hospitalization rate, and better pulmonary function than the patients who received a placebo (Simakajornboon and Davis, 1998). Other studies found that high doses of ibuprofen have similar effects as prednisone but with fewer side effects (Marshall and Samuelson, 1998).

In cases of severe lung disease wherein the patient is suffering from respiratory failure, lung transplantation has become an accepted treatment option. In most CF patients, survival rates after transplantation are as good or better than survival rates of patients with other types of pulmonary disease who receive lung transplants (Simakajornboon and Davis, 1998). Lung transplantation has provided a new option for CF patients who are suffering from severe respiratory disease.

B. Treatments to Improve Digestive Problems

Most cystic fibrosis patients die of lung disease, but in the past the majority died because of digestive problems. Now, however, the digestive problems afflicting patients can be managed fairly easily.The three most important factors for improving nutritional status are a high calorie diet, vitamins, and pancreatic enzyme supplements (NHLBI, 1999). Physicians usually prescribe a high-fat diet that provides about 200% of their daily recommended calories (Rosenstein and Zeitlin, 1998). In cases of severe malnutrition, the physician often recommends oral or intravenous supplements that are predigested and have an extremely high number of calories (Alemzadeh, et al., 1998). In oral treatments, pancreatic enzyme supplements are taken with meals to aid in proper digestion. Unfortunately, the pH in the intestines of CF patients is lower than it is in normal individuals, so the enzymes are not completely effective and much of the consumed food goes undigested (Marshall and Samuelson, 1998).

V. MOVING TOWARDS A CURE

Although there is currently no cure for cystic fibrosis, research on possible cures is proceeding in several directions. The goal of much of today’s research is to discover a mechanism that would promote proper ion transport in cells that express CFTR. There are two major avenues of research that promise to produce a cure for CF. The first of these is gene therapy, and the second avenue is called protein assist therapy (Cystic Fibrosis Foundation, 1999).

A. Gene Therapy

The primary goal of gene therapy is to deliver a normal copy of the CFTR gene to cells so they can express the protein, essentially curing cystic fibrosis (Rosenstein and Zeitlin, 1998). Specifically, researchers are attempting to deliver the gene to the epithelial cells in the lung since virtually all of the mortality seen in CF occurs because of lung disease. Currently, researchers are investigating three different vectors for delivering the gene: adenoviruses, adeno-associated viruses, and liposomes, (Simakajornboon and Davis, 1998).

Gene therapy through adenovirus vectors has been somewhat successful, but there are several problems that occur with this kind of treatment. In this form of gene therapy, an adenovirus is modified by removing its genetic material so it cannot cause disease. Next, a normal copy of the CFTR gene is inserted into the virus, and finally the virus is introduced into the airway (Cystic Fibrosis Foundation, Gene Therapy, 1999). These viruses naturally infect the epithelial cells in the airway, so they can be quite effective for delivering the CFTR gene (Simakajornboon and Davis, 1998). One of the problems with delivering the gene through viral vectors is that the virus tends to cause an immune response in the individual receiving treatment (Resnikoff and Conrad, 1998). Usually, the gene ceases expression shortly after the immune response is initiated (Simakajornboon and Davis, 1998).

More recently, adeno-associated viruses and liposomes have been used as vectors for delivering CFTR to lung epithelial cells. Liposomes are small fat capsules in which the gene is inserted and which do not cause disease (Resnikoff and Conrad, 1998). Likewise, adeno-associated viruses are viruses that normally infect the epithelia of the lungs, but they are not disease causing because they cannot reproduce themselves (Rosenstein and Zeitlin, 1998). These vectors may prove to be advantageous over adenoviruses because they do not initiate the immune response and inflammation seen with adenovirus vectors (Simakajornboon and Davis, 1998).

Current research surrounding gene therapy is focused on solving the many problems with delivery of the normal gene. To solve the problems with viruses initiating an immune response, researchers are looking for new viral vectors and attempting to temporarily suppress the immune reaction (Resnikoff and Conrad, 1998). There are still many problems surrounding gene therapy as a cure for cystic fibrosis, but through continued research, replacing the defective CFTR gene should be possible.

B. Protein Assist Therapy

A second line of research in cystic fibrosis that holds promise is protein assist therapy. One major form of protein therapy is the use of various drugs that increase the amount of CFTR reaching the surface of the cell (Rubenstein and Zeitlin, 1998). It is known that CFTR protein with the deltaF508 mutation is still capable of functioning almost normally, but almost all of the protein gets degraded before it has the chance to reach the surface of the cell. CFTR activity is cAMP dependent, so one possible way to increase its expression is through phosphodiesterase inhibitors (Resnikoff and Conrad, 1998). Phenylbutyrate, a drug use to treat other disorders, is known to increase the expression of CFTR, so it may also be effective for use in this manner (Simakajornboon and Davis, 1998). These forms of treatment are advantageous over gene therapy because they make it possible to treat all affected tissues at the same time (Buchwald, 1996). A second kind of protein therapy is to deliver normal CFTR protein directly to the epithelial cells. The protein can be delivered through various vectors similar to those used for gene therapy such as liposomes and viruses. Once the normal protein is delivered to the cell, it can function as if the cell actually produced the protein. So far there has been only limited success with this method (Simakajornboon and Davis, 1998).

VI. CONCLUSIONS

Cystic fibrosis is of particular interest to me not only because it is the most prevalent genetic disease in the United States, but also because the disease has struck my family. I have a young cousin with cystic fibrosis, and I did not realize the seriousness of his condition until recently. Although CF is usually fatal by the time an individual is thirty, there are advances in treatment all of the time that are extending the expected life span for CF patients. Additionally, these refined forms of therapy are improving quality of life for individuals with CF so they can lead nearly normal lives.

The most exciting advances in CF research center on curing the disorder. There are hundreds of researchers working around the world who are trying to find a way to cure cystic fibrosis. It is likely that within the next decade or two both gene therapy and protein assist therapy will be further developed making them effective means for restoring normal airways to CF patients (Laag 1996). Since my cousin with cystic fibrosis is only eleven, it is quite likely that a cure for cystic fibrosis will become a reality in his lifetime, and hopefully, he will be able to lead a long, healthy life.

Top