The Cystic Fibrosis Gene. about. CF is one of the most common genetic diseases that cause death in both children and

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1 Gill1 Peter Gill Malory Klocke Research Paper 02 August, 2011 The Cystic Fibrosis Gene Cystic fibrosis, better known as CF, is a genetic disease most people know very little about. CF is one of the most common genetic diseases that cause death in both children and young adults. The average life span for people with CF is about years of age. CF mainly targets the respiratory and digestive system. This can lead to many complications such as a shorter life span filled with daily treatments and multiple hospital stays. Since the discovery of the gene that causes CF, there have been many great improvements in the treatment and diagnosis of cystic fibrosis. Being able to find and correct the defected gene has lead way to new drugs and research that could possibly cure CF and not just treat its symptoms. Cystic fibrosis is a life limiting disease that affects about 1 in 1,900 Caucasians, and 1 in 12,000 African Americans in the United States (Mitchell 4). CF is very uncommon in all other races. People of northern European descent have the greatest risk of being born with CF. Cystic fibrosis was discovered in 1935 by Dr. Dorothy Andersen. It was found when she was performing a postmortem examination of a child who was thought to have died from malnutrition (Robinson). CF mainly affects the lungs and pancreas by creating an excess of thick clogging mucus. In the lungs, the mucus makes an ideal breeding ground for respiratory infections and clogs air passages. In the pancreas, the mucus clogs the ducts that project the enzymes to digest food. This is what leads to malnourishment. The liver and intestinal tracts are

2 Gill2 then affected because of the pancreas deficiency causing them to fail. Fertility can also be affected due to excess mucus in both the male and female reproductive systems. It took scientists over 50 years to finally find the gene that caused CF. In 1989, the gene was identified and named the cystic fibrosis transmembrane conductance regulator or CFTR for short (Mitchell). Within the CFTR gene there are nearly 800 different mutations or defects currently known. However nearly 70 percent of the CF population has the same defect known as the delta F508 gene (Robinson). CFTR is a protein found at the surface of many tissues affected by CF. Its main purpose is regulating the flow of water and ions in and out of the cells. When the CFTR gene is not working properly in patients with CF, salt and water are not able to enter the tissues properly, thus causing the natural fluids to become the thick mucus mentioned earlier. Diagnosing cystic fibrosis is usually done at an early age, but there is the occasional adult that is diagnosed. Children and infants with persistent intestinal problems leading to malnutrition or abnormal stools are top candidates for CF screening (Mitchell 7). Children with chronic coughs and frequent lung infections are front runners for testing as well. Infants with a family history of cystic fibrosis are usually screened before they leave the hospital, whether they are showing symptoms or not. As of 2001, the median age at diagnosis was six months and the predicted survival age was 33 years (Mitchell 7). My sister was diagnosed at the age of 25 after having persistent respiratory complications. The rest of my siblings, including myself, were tested and out of the five of us, I too tested positive for CF. The most common test that is used is called a sweat test (Robinson). A chemical is rubbed on a small portion of skin, and is then covered with a piece of special material. The area is then stimulated constantly with a small electric shock, making the skin sweat (Mitchell 8). After about 20 or 30 minutes, the material is removed and the amount of sweat accumulated is

3 Gill3 checked for abnormally high concentrations of salt (Robinson). People with cystic fibrosis have a much higher level of salt in their sweat than those without CF. Another less common way is to take a sample of DNA from the individual to be tested. The DNA is examined for the CF mutation on both CFTR genes. The only problem with DNA testing is there are only 25 mutations that are identifiable (Mitchell 8). If the person in question does not carry one of these common mutations the test will be inconclusive and left up to the doctor for interpretation. Thanks to modern science, people worried they could be carriers can be screened for the 25 common mutations. Anyone planning on having children should consider genetic screening if there is any family history of CF. Cystic fibrosis is a genetic disease that requires each parent to be a carrier. Carriers of CF carry one normal CFTR gene and one defective gene. Only one normal gene is needed for the CFTR protein to function correctly. If both parents are found to be carriers of the CFTR mutation, they have a one out of four chance of having a child with CF (Mitchell 9). The same parents also have a 75 percent probability of having a baby without cystic fibrosis. Approximately one in every 25 Americans of northern-european descent is a carrier of the mutated CFTR gene (Robinson). Prior to the discovery of the CF causing gene, the treatments did not target the source itself, only the symptoms of cystic fibrosis. Life spans were also much shorter as a result of no known source for the disease. On average most people with CF were lucky to make it past their teens. The majority of people diagnosed with CF had a poor quality of life. They were stuck in hospitals for the greater part of their life with respiratory infections and digestive complications. The treatments have been steadily improving over the past several decades (Robinson). Before the source was found, scientists and doctors could only treat infections and complications of CF, not the causes.

4 Gill4 CF causes pancreatic failure making it almost impossible to gain and at times maintain a healthy weight. To assist and help with the digestive process, CF patients are given several enzymes to take with each meal, sometimes up to 20 pills. Multi vitamins are also a staple to help combat the malnourishment that goes along with cystic fibrosis. CF infected people are generally on a very high calorie diet as well (Robinson). These treatments are not enough for some with cystic fibrosis who are not able to absorb enough nourishment. For most of these people, a temporary, or for severe cases, a permanent feeding tube is needed to help them get the essential nutrients and medications needed to maintain a healthy lifestyle. The respiratory preventative treatments consist of several inhalers and a series of percussions to the chest, which involves a device that vibrates at a high rate of speed to help loosen mucus in the lungs. The idea is to loosen up the mucus, so it can be coughed up, in an attempt to prevent any infections in the lungs. It is absolutely vital to sufferers of CF to take care of their lungs. Almost all deaths due to cystic fibrosis are caused by the damage done to the lungs from chronic respiratory infections. Perhaps the biggest breakthrough since the discovery of the CF causing gene is the development of a new drug called VX-770. Developed by Vertex Pharmaceuticals, VX-770 is designed to treat the underlying cause of CF (Cystic). For the first time, a drug has been developed to hopefully correct the function of the CFTR gene. VX-770 only targets a small percentage of CF sufferers that have one of the rarer genes called the G551D mutation, or also known as the Celtic Gene (Queen s). The G551D mutation only affects about 1.6 percent of the CF population, mainly in people of Irish descent (Mitchell 8). But this is still good news, and opens the door to develop similar drugs for the more common mutations.

5 Gill5 In March of 2011, all clinical trials were completed with very positive results. For the study they used two groups; adults age 12 and up and children ages 6 to 11. The adult group were then separated into two groups. One group received the VX-770 drug and the other received a placebo. The group that received the placebo showed no signs of improvement, while the group receiving the drug showed great progress (Cystic). Both the adults and children receiving the VX-770 showed great improvements in lung function, salt reduction, and weight gain (Cystic). These trials were conducted in Europe, USA, and Australia with the same significant results (Queen s). The drug has been sent to the FDA for approval, hopefully it will be available by the end of the Discovering the CF causing gene is what made VX-770 possible. The development of this drug is significant because it is the first to show that treating the underlying cause of cystic fibrosis may have profound effects on the disease, even among people who have been living with it for decades (Queen s). The most important result was the reduced amount of salt in the sweat. This reduction implies that the drug is actually correcting the CFTR protein function. Even though Vertex Pharmaceuticals is not calling this a cure it gives those of us with CF a new hope. Unfortunately, for people with cystic fibrosis it is too early to tell if the new drug will lengthen the average lifespan (Queen s). The results would imply that it will probably increase the average age of mortality, even for those who have reached adulthood already. After the promising results of VX-770, Vertex Pharmaceuticals has already begun to develop another drug called VX-809. It is designed to hopefully help correct the CFTR gene even more than VX-770. The VX-809 drug is designed to target more than one mutation of cystic fibrosis as well. Currently they are combining the two drugs to treat the most common form of CF, the delta F508 mutation (Cystic). If the combination is successful nearly three

6 Gill6 quarters of the CF population could be treated with this ground breaking drug. It might not be a cure but it is definitely a step in the right direction. The discovery of the CFTR gene has helped the progress of major advancements in treatments for CF (Mitchell 10). Prior to knowing the cause of cystic fibrosis doctors could only monitor and treat the side effects that the CF was causing. Now they know exactly what is causing the complications and are able to combat the affects at their source. Many new drugs have been developed to help minimize lung infections and intestinal complications. The new drugs will help compensate the lost function of the CFTR gene. Although the discovery of the CF causing gene has made huge breakthroughs possible, there is still no known cure.

7 Gill7 Annotated Bibliography "Cystic Fibrosis Foundation - FAQs About VX-770." CFF.org. 10 June Web. 01 Aug The CF foundation is a made up and contributed to by many doctors and experts of cystic fibrosis. The cite gives massive amounts of information on the new drugs being developed to combat CF. The VX-770 is the closest thing to a cure there has ever been for CF. The positive results from the clinical tests have shown great improvements in vital areas. Sodium levels in sweat have decreased; pulmonary tests have shown greater lung capacities and patients even gained weight. The discovery of the CF gene is what has made such advances possible. I can use the information to give explanations as to what the VX-770 drug does for CF. This information will also help me show the importance of targeting the source rather than the symptoms. I will also use the information to show how this new drug is already giving way to new drugs targeting the source of CF. Mitchell, R. Michael H., and Jonathan A. Cohn. "The Science behind the Disease." Beyond Lungs Meeting the Needs of Adults with Cystic Fibrosis. Ed. Annie McKenna and Howard Goldsweig. Hannover: Felsenstein CCCP, Print. R. Michael H. Mitchell is a consultant gastroenterologist at Belfast City Hospital Trust in Belfast, Northern Ireland. Jonathan A. Cohn is a professor at Duke University Medical Center in Durham, NC. Cystic fibrosis (CF) is a genetic disease that causes damage to the lungs, pancreas, intestines, and liver. The discovery of the CF gene has led to substantial advancements in the treatments for the disease. The Gene s discovery has also led to advancements in the diagnosis of CF. The Science Behind the Disease gives good insight into the benefits of discovering the CF gene and how it has helped advance

8 Gill8 treatments for those suffering from the disease. It also gives some explanations into what the disease is and does to people with CF that I will incorporate into my research. I can use this source to show how important the discovery of the CF causing has been for advancements in treatments. Robinson, Richard. "Cystic Fibrosis." The Gale Encyclopedia of Medicine. 3rd ed. Vol. 2. Detroit: Gale, Gale Virtual Reference Library. Web. 30 July Richard Robinson is an expert on cystic fibrosis and has a daughter with the genetic defect. CF is a genetic disease that causes respiratory and digestive complications. Cystic fibrosis is the most common life shortening genetic disease in the United States. Discovered in 1935 the life expectancy has steadily increased with advancements in treatments. I can use the general information from this source to explain the effects of CF. The information I use from the source will give the simple explanations CF has on the people carrying this defect. Queen's University, Belfast. "First ever drug to treat Celtic Gene in cystic fibrosis sufferers." ScienceDaily, 20 Jun Web. 29 Jul Queens University is the leading research facility for VX-770 in Ireland. The new drug only treats a small percentage of people with the G551D gene type also known as the Celtic Gene. The drug VX-770 is the greatest breakthrough in cystic fibrosis since the discovery of the gene causing it. This is the first drug to target the source of the defect rather than the symptoms. Although VX- 770 only targets a small percentage of the CF population it is the first step towards a possible cure for cystic fibrosis. I will use this story to give the factual data collected from the clinical studies. This information will allow me to speculate the possible implications this new technology will have on the future of CF.