An Overview of Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is the most common lethal genetic disease of Caucasians. which causes certain glands to malfunction. In CF mucous glands produce a thick. sticky mucus which interferes with breathing and digestion. Mucus clogs passages in lungs and ain/vays. causing breathing difficulty. chronic coughing, and sometimes heart failure. Mucus also blocks ducts in the pancreas. preventing digestive enzymes from reaching the intestines. and it may also clog the liver and digestive tract. Today about 30.000 people in the United States live with cystic fibrosis.

CF is recessrvely inherited with a carrier rate of around one in twenty-five. and has an occurrence of one in 2,500 live births (Wolf 1), The majority of the people in the United States do not understand the severity of cystic fibrosis and that it is a serious genetic disorder. Clinical symptoms for CF are caused by the obstruction of organ ducts by the abnormal secretions.

They consist of such symptoms as chronic obstructive airways disease pancreatic insufficiency and malabsorption high electrolyte concentrations in sweat.

sterility due to vas deferens obliteration and subclinical cirrhosis of the liver . However as the severity of these symptoms varies in different patients and because of the presence of normal lungs after birth it is difficult to make an early accurate prognosis. The presence of mucus in the lungs provrdes a site where bacteria or viruses are easily caught. but which are not removed from the lung by the action of the bronchial cilliary epithelium. ln CF the mucous layer becomes so Viscous that the cilia can no longer move it.

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This leads to supradded infections. Progressive ainlvay obstruction and inflammation causes hypoxia a reduced lung vital capacity and eventually over months or years hypercapnia (chronic respiratory failure) which usually leads to death.

It has been mentioned that the basic defect in cystic fibrosis is due to abnormalities in the secretions of the exocrine glands. These glands all produce a protein-containing fluid which has either a digestive. lubricative or protective function . The normal content of this fluid is affected directly by the ionic. protein and water composition of the epithelial tissue concerned. which are crucial to correct the functioning of the tissue. The amount of water in the secretions are dependent upon movement of ions across the cell. In normal secretory tissue. chloride ions enter the lumen from the extracellular space via the epithelial cells. this creates an increased negative potential across the epithelial cells which results in the transport of sodium ions down the potential gradient into the lumen. This increased concentration of ions in the lumen means that water travels by osmosis into the lumen from the extracellular space.

It is known that in CF the luminal side of the affected exocrine glands are more negative than normal. due to marked decrease in the permeability of the cell to chloride ions. this was first shown by an increased concentration of sodium chloride in the sweat of CF patients. This causes an increased uptake of sodium ions. known to exist in CF nasal tissues. contributing further to the negative ionic potential. The increase in chloride ions and decrease in sodium ions affects the osmotic movement of water into the ainivay by decreasing it and thereby increasing the viscosity of the mucous secretions. One proposed scheme of chloride. sodium ion and watertransport across epithelium. The abnormal negative potential is caused by the defective protein which is the chloride ion channel called cystic fibrosis transmembrane conductance regulator (CFTR) , The CFTR protein is encoded by a gene , approximately 230 kb of DNA long With 27 exons, which is located on the long arm of chromosome 7.

CF is caused by a defect in this gene and while many different defects cause CF, a lot of these seem to be race and creed specific, one the most common Caucasian forms is due to a 3 baserpair deletion in exon 10 of the gene, which is the loss of a phenylalanine residue at position 508. This defect is known as Delta F-508. CFTR is a cAMP-activated integral receptor protein that allows the transport of chloride ions across the luminal cell membrane, although the abnormal CFTR seems to prefer iodine to chlorine . it has four core nucleotide»binding domains that bind ATP, the hydrolysis of which causes a conformational change in the protein that opens the channel. It is an important detail that the transport of chloride ions is not active transport. but instead is channeHike. in addition to the four domains which are similar to those found in other ATP—binding transporters, the CFTR gene is different in that it contains a unique regulatory or R domain.

This domain is highly charged and contains four phosphorylation sites which respond to changes in cAMP levels by opening the channel. The affect of defects in the CFTR protein can affect these sites and if all four are unable to be phosphorylated then the channel cannot be opened (Abramowicz 2). The representation is one of the R-domain blocking and unblocking the channel in response to variations in cAMP (Figure 3). Figure 3 – Representation of CFTR with R-domain opening and closing channel. An abnormal CFTR has some unknown effect stopping chloride ions from crossing the epithelium, This combined With the presence of other chloride ion channels demonstrates that in some cases no CFTR is better than abnormal CFTR. Different mutations have different effects either on the CFTR or. rarely, related processes, examples affecting the Redomain phosphoiylation. the ATPrbinding domains, the channel domains themselves, or the localisation and stability of CFTR within the membrane.

Current treatment of CF is only symptomatic and prophylactic. The primary concerns of any treatment are With the life-threatening aspects of the disease, which are the pulmonary manifestations ln this case. Postural drainage, chest percussion, breathing exercises. and the use of inhaled saline or distilled water. are used to clear the bronchial secretions. and antibiotics are used to treat the acute infection caused by the lack of mucus clearing. Bronchodilators. in addition to helping to relieve associated asthma, enhance the efficiency of the mucociliaiy transport in the lungs. GI symptoms are relieved by controlled diet, increased protein and vitamins. and oral pancreatic enzymes, to control malabsorption. The current treatment fails because it is does not treat the actual cause of the disease, the mutated CFTR. Gene therapy is a possible future solution to CF, as it has been shown that a single copy of cDNA carrying a normal CF gene into an abnormal cell restores normal cAMP-dependent chloride transport.

However, although the gene is available in sufficient quantities, the problem remains of how to deliver the correct therapeutic dose of any drug to enough of the affected cells. The methods of DNA transfer that presently exist involve: the physical introduction of DNA directly into cells with a high efficiency, but it is very labour intensive; using the chemical interactions of DNA, ligand conjugates and the cell membrane. a process that is very efficient. non» toxic and selective, but which needs to a lot more work: and using biological intermediates such as viruses, Viral vectors have been developed, with adenowrus and liposome systems working in vitro. Methods based on liposome-mediated gene transfer show some success in clinical trials. An increase in the permeability of the CFTR to chloride ions of 20% was seen in CF patients who received a liposome complexed wrth cDNA encoding the CFTR gene.

However was noted that the sample size was very small and the delivery mechanism and success rate had to be improved. In contrast. while the use of Viral vectors has been shown to be more successful, the method of targeting is much less exact and thus Viral solutions are more toxic and there is some risk of tumour formation. Retroviruses, which only target dividing cells, have the added disadvantages that, they are likely to only affect terminally differentiated cells. and, they can disrupt important genes. Due to the limited size of viruses there is a limitation to the amount of foreign DNA that can be added. However, an experiment using an adenovvus, with the full CFTR cDNA sequence, planted into the lung epithelium of a rat showed correct CFTR chloride ion permeability in all affected cells.

suggesting that improvements in targeting and toxicrty Will make the use of Viral vectors for the treatment of CF a certainty. Most of the causes and effects of CF are now understood, but until the treatment deals directly with the abnormal CFTR. CF will still be a disease with a high mortality rate. Gene therapy. either using liposomes or Viruses, demonstrates the best chance of successful treatment in the future. However, they both still have a long way to go, and the moral issues of gene therapy still need to be solved. As we wait for cures to be found helpless victums of cystic fibrosis continue to die at early ages because we are not aware of the severity of this Vicious disease.