Cystic Fibrosis

¶ … cystic fibrosis. The writer takes the reader on an exploratory journey about cystic fibrosis and its causes, treatments and future. The writer outlines many aspects of the disease including the enzyme treatments that are currently being studied. There were five sources used to complete this paper. The medical community has made many amazing discoveries in the last few decades. People are living longer than ever before and the quality of their life has improved along with the quantity.

There are many disorders and diseases that are now considered curable or manageable that were once considered fatal. Cystic Fibrosis is a disease however that has baffled the medical community for many years (Santis,2000). Locating its cause, discovering a cure and other pertinent goals have been targeted by research around the world with little success. In recent years however the genetic link and mapping of cystic fibrosis has been pursued with a measure of success and more recently genetic enzyme therapies have shown themselves to be extremely promising.

Before one can begin to examine and understand the implications and future of enzyme therapies and genetic implications one first must have an understanding of cystic fibrosis itself. Cystic fibrosis is a life-long, hereditary disease that causes thick, sticky mucus to form in the lungs, pancreas, and other organs (Santis, 2000). In the lungs, this mucus tends to block the airways, making breathing difficult. In the pancreas, it clogs the ducts leading to the intestines, thus interfering with the digestion of fat.

It is the leading genetic killing disease in the nation with 30,000 Americans having it currently. It is not particular about gender and strikes males and females equally often. It is also not picky about what race it affects, though studies indicate that there are more white people with the disease than there are other races with it. The disease is started at conception but it can take many years to show itself after the person is born.

Out of all the people born in the United States each year with Cystic Fibrosis symptoms at birth are only present between 10 and 15% of the time. Diagnosis is sometimes delayed for decades because of the mildness of the symptoms or a failure to recognize them. Cystic Fibrosis is a genetic disease with nearly 12 million carriers doing the work for it in the United States alone. In order for a child to inherit the disease both parents have to carry the gene.

When both parents carry the cystic fibrosis gene there is a twenty five percent chance that the child will inherit and develop cystic fibrosis. There are documented cases where one parent has a healthy gene, which ends up dominating the defective gene, and the child lives symptom free and disease free. There are many symptoms to the disorder depending on the severity of its infliction. Some symptoms include wheezing, coughing, and many bouts of pneumonia, salty tasting skin and clubbed fingers and toes.

In addition there may be a failure to thrive and the child may lose weight even though he or she eats a balanced diet. Testing the child for the cystic fibrosis gene and measuring the salt content o the sweat can diagnose the disorder. If it is diagnosed early treatment is the best preventive medicine for that child. Although there is still no cure for cystic fibrosis, a variety of treatments can ease its symptoms.

The options include physical or pulmonary therapy (draining of the lungs), exercises to help loosen mucus and stimulate coughing, medications such as bronchodilators to improve the passage of air into the lungs, mucus-thinning medications (called mucolytics), and antibiotics to kill infection-causing bacteria.

To help make the child more comfortable, parents can learn how to perform procedures such as physiotherapy at home (Ricks, 1997)." How is cystic fibrosis diagnosed? In addition to a complete medical history and physical examination, diagnostic procedures for cystic fibrosis include a sweat test to measure the amount of sodium chloride (salt) present. Higher than normal amounts of sodium and chloride suggest cystic fibrosis. Cystic fibrosis is a disease that takes the lives of the young (Ricks, 1997).

To date there are only 14 people alive in the nation who are past the age of 60 with the cystic fibrosis (Ricks, 1997). "The oldest known patient is 70, according to the Cystic Fibrosis Foundation in Bethesda, Md., which maintains a national registry of patients. A research team in Iowa is running tests on a patient who is 83 and may have the disorder.

Specialists say doctors need to be aware that adults who have suffered repeated bouts of pneumonia, chronic bronchitis and other lung infections may have mild cystic fibrosis (Ricks, 1997)." These patients are the exceptions (Ricks, 1997). The disease gives the victim an average lifespan of 31 years according to experts (Ricks, 1997). It affects one in every 2,400 infants and is much more prevalent in Caucasian infants than any other race. The disease makes the body produce thick viscous fluid (Ricks, 1997).

This fluid obstructs the several of the body's systems that include the lungs, the pancreas and the sweat glands (Ricks, 1997). There are also gastrointestinal tract blockages (Ricks, 1997). One of the symptoms of the disease is the salty sweat the sufferer has throughout their life (Ricks, 1997). This is caused by the disease forcing high concentrations of chloride through the system, which is excreted by sweat (Ricks, 1997). "The primary cause of death in cystic fibrosis is from lung disease (Ricks, 1997).

Males with cystic fibrosis are invariably infertile because of obstructions in reproductive organs. There are a number of ways to test for the disease, doctors say, including genetic screening, which became available shortly after CFTR was discovered. Another method is measuring salt concentrations in sweat (Ricks, 1997)." Currently it is believed that there are 30,000 people in the United States who have the disease, including 1 in every 17,000 newborn blacks and 1 in every 30,000 Asian newborns (Ricks, 1997). Within the last decade there have been many studies about the genetics of Cystic Fibrosis (Nance, 1992).

In 1989 there was an identification of the Cystic Fibrosis gene. It was discovered shortly thereafter that the gene had approximately 700 different mutations (Nance, 1992). When the gene was discovered the experts began to recommend that all family members of victims of CF receive testing to determine whether or not they were carriers (Nance, 1992). "A single mutation, denoted DeltaF508, is found in approximately 70% of carriers of European ancestry. Currently, over 160 other mutations have been identified (Nance, 1992). Many of these are extremely rare, but a few reach frequencies of 1% -3% of CF carriers.

Current surveys indicate that 85%-90% of CF carriers in the North American white population can be detected by testing for 6-12 mutations (Nance, 1992). The detection rate is even higher in some populations (e.g., Ashkenazi Jews) but is substantially lower in blacks, Hispanics, and Asians. In view of this mutational heterogeneity, it is unlikely that DNA-based CF carrier detection rates will exceed 95% in the foreseeable future (Nance, 1992).

" The recommendations regarding the disease are currently as follows (Nance, 1992): Although the sensitivity of carrier testing for CF has improved and pilot studies are under way, CF testing is not recommended, at this time, for individuals or couples who do not have a family history of CF (Nance, 1992). Individuals with a positive family history of CF or who have a blood relative identified as a CF carrier should be offered CF testing with appropriate education and counseling.

Optimally, carrier testing should be offered prior to conception, to provide a couple the broadest range of reproductive options (Nance, 1992). When indicated, CF counseling and testing should adhere to the following guidelines (Nance, 1992): Screening should be voluntary, and confidentiality must be ensured (Nance, 1992). Screening requires informed consent. Pretest education should explain the benefits and hazards (e.g., stigmatization and possible loss of insurability) (Nance, 1992). Providers of screening services have the obligation to ensure that adequate posttest counseling is provided (Nance, 1992).

Quality control of all aspects of laboratory testing, including systematic proficiency testing, is required. As with all indicated health-care services, there should be equal access to testing (Nance, 1992). Efforts should be expanded to educate health-care providers and the public, regarding the complexities of CF screening in particular and issues involved in genetic health-care services in general (Nance, 1992). With the newly discovered genetic mapping of the disease the medical community began to move quickly in the direction of new therapies to treat the disease with. (Cooke, 1993).

There have been discoveries and encouragements along the way (Cooke, 1993). One of the discoveries was that there are people with the CF gene and diseases who have what appears to be a mild case (Cooke, 1993). The genetic recognition of the disease opened the door to many possibilities of therapies and treatments for those who suffer its consequences (Cooke, 1993). Once the gene was understood the next step was more clearly mapped out for the medical field (Cooke, 1993).

The illness results when the gene - called the cystic fibrosis transmembrane conductance regulator (CFTR) gene - fails to make its normal protein product. The gene is unusually large, making a protein that consists of a chain of 1480 amino acids (Cooke, 1993). Normally, the protein folds up to form a pore-like duct that becomes part of a cell's outer membrane (Cooke, 1993). The number of mutations found on the gene has escalated in the past four years, Tsui said.

So "we now have to make up our minds which mutations actually cause disease (Cooke, 1993)." "The most common mutation causes about 68% of all cystic fibrosis cases (Cooke, 1993). That mutation, called D508, is seen once in every 30 whites, and occurs when the amino acid that is supposed to be at position 508 is missing (Cooke, 1993). Most of the other mutations are quite rare and cause few cases of cystic fibrosis (Cooke, 1993). But one, called R117H, has turned out to be much more common than anticipated.

It appears to sometimes cause cystic fibrosis, male sterility and perhaps chronic bronchitis and chronic sinusitis (Cooke, 1993). Cutting said that a recent screening test, run by the Kaiser-Permanente health maintenance organization in California, found that "R117H is nineteen times higher [more prevalent] than expected (Cooke, 1993)." The genetic factor of the disease is an important one which gives rise to the therapies that are being currently tried. The genetic factor of cystic fibrosis has been an extremely complicated process to map out for the medical community.

While scientists knew there were genetic components, which were directly responsible for the disease and its existence, they had a difficult time locating exactly where it fell on the genetic and DNA continuum of life (Santis, 2000). Because it was so difficult to locate the exact specifications for the disease scientists concentrated instead on identifying the protein that indicated Cystic fibrosis when it became abnormal. Chromosome I was examined as was genetic material that is located within saliva to no avail.

The search continued to include cytogenetic studies as well as chromosomal abnormality studies in the effort to locate the genetic perpetrator of this deadly disease (Santis, 2000). He search moved to the brain and various glands of the body including the adrenal gland with no success. The next step was to identify cloned fragments of DNA for conserved sequence and then determining several common factors of this sequence scientists were then able to isolate several genes as Cystic Fibrosis candidates (Santis, 2000).

Through testing of the various candidate genes the scientists discovered what was the most likely gene responsible for the Cystic Fibrosis gene.

In addition there was a protein isolated that was later named the CPTR or the "Cystic Fibrosis Transmembrane Conductance Regulator (Santis, 2000)." A year later there was final proof obtained that the correct gene had been located and identified for the disease when the expression of the normal CFTR DNA in Cystic Fibrosis epithelial cells caused a correction of the chloride transport defect that is so typical of Cystic Fibrosis (Santis, 2000). Once the correct gene and protein was determined the search for the exons moved forward.

The initial phase of study uncovered 27 exons (Santis, 2000). Out of those 27 it was determined that number 13 was by far the largest (Santis, 2000). These discoveries led to the understanding of the genetic implications of the disease which opened the door to try and locate a gene based therapies for the maintenance of the disease as well. Until recently the only treatments available for the disease were antibiotics and mucous thinners (Stanford, 2001). They did not do the job as well as doctors hoped that they would.

Recent medical research breakthroughs have developed an inhalant that controls the patient's immune system response to infection (Stanford, 2001). By administering the molecule as an inhalant, the researchers hope to confine its effect to immune cells in the lung and avoid adverse side effects associated with injections of the compound (Stanford, 2001). " The life span of a cystic fibrosis patient has been lengthened, as has the quality of life for that patient.

There was a time when the quality of life for a person with cystic fibrosis was extremely limited because of the problems the disease presented to the person who had it. Often times breathing issues prevented any real life quality while other things such as susceptibility to infection and the need to avoid those interfered with quality of life issue. Today, medical science has advanced enough that the life span expectancy has been doubled and the quality of life for those with the disease has improved tremendously.

It is still however a very deadly disease. The life expectancy in the United States for a non-affected person is in the 70's. The life span of a person born with cystic fibrosis is usually around 33 years of age. Other researchers have found that the severity of lung damage in cystic fibrosis patients correlates inversely with the amount of gamma interferon they produce - less gamma interferon means more damage (Stanford, 2001). "It's really one of the most important cytokines that the body uses to fight off infection," said Moss (Stanford, 2001).

But gamma interferon's ability to affect cells throughout the body makes it difficult to restrict its activity when used clinically - especially when delivered by injection (Stanford, 2001). However, the nature of cystic fibrosis makes it possible to limit the effect of the molecule (Stanford, 2001). "When interferon is injected it has a moderate amount of toxicity throughout the body and it sometimes causes a flu-like reaction. However, cystic fibrosis patients inhale it directly into the lungs and it doesn't go into the rest of the body," Moss said.

In preliminary tests, patients with tuberculosis and asthma tolerated the inhaled gamma interferon well, and there was little evidence that it was active in the bloodstream, he added (Stanford, 2001). Researchers hope gamma interferon will block the destructive cycle of infection and inflammation in the lungs of cystic fibrosis patients by simultaneously stimulating the infection-fighting properties of one type of immune cell (lung macrophages) and suppressing the activity of another (neutrophils) that cause airway inflammation and destruction (Stanford, 2001).

Researchers at Stanford administered the first dose of gamma interferon less than three weeks ago. Eventually 60 cystic fibrosis patients at eight medical centers around the country will participate in the double-blinded, phase-II trial structured to test the safety and efficacy of gamma interferon (Stanford, 2001). Approximately one-third of the patients will receive a placebo, and the remaining two-thirds will be split into two groups to test two different dosages of gamma interferon.

Patients will be treated three times per week over a period of three months, and researchers will monitor lung function as well as the extent and severity of infections (Stanford, 2001)." One of the newest treatments being examined for cystic fibrosis involves the use of enzyme therapy. Research has been using restriction enzymes Hpall and Mispl for the purpose of therapy in research CF trials. There has been a measure of success as well as interesting findings regarding the use of these two enzymes in treatment possibilities.

CoQ1O, ubiquinone) Coenzyme Q10 is a lipid-soluble quinone present in every cell in the body. During intracellular respiration, CoQ10 collects reducing equivalents and is then converted to the reduced form, Coenzyme QH2. The immune-enhancing effects of supplemental CoQ10 include an increase in granulocyte proliferation, and an increase in overall macrophage activity (Folkers, 1992). The most interesting effects are a prolonged survival of mice infected with P.

aeruginosa.61,62 This might be connected with the ability of CoQ1O to increase antioxidant protection in cell membranes, as well as to function at Golgi and plasma cell membrane sites in secretion-related membrane flow and growth control (Folkers, 1992).63 Via its antioxidant activity, CoQ10 also assists in recycling and sparing vitamin E64 Thus, in humans with CF, CoQ10 could prove to be an adjunct in the demanding treatment of P. aeruginosa infections and in better control of the inflammatory immune response.

Suggested dosage of CoQ10 is 60 mg to 100 mg per day (Folkers, 1992)." Gene treatment is designed to attack the root of the problem instead of just treating the symptoms as they arise. Gene therapy using enzymes is the most promising and exciting breakthrough in many years regarding the therapy for the disease. The therapy was originally tested in a lab when cloned genes were introduced to actual genes and the results were very promising (Gene, 2002).

The next landmark step was taken in the spring of 1993, when the first experimental dose of a gene therapy treatment was given to an individual with CF (Gene, 2002). This study was launched at the National Institutes of Health (NIH) and supported by the Cystic Fibrosis Foundation. It marked the first time that scientists were.