Category: Cystic Fibrosis

Out of billions of people in the world, 1 out of 100,000 is suffering from сystic аibrosis, a progressive genetic disease that causes lung infections and limits the ability to breathe. This is because сystic аibrosis affects the cells that produce mucus, sweat and digestive juices, and causes the fluids to become thick and sticky. They then cover the tubes, ducts and passageways in the lungs. This genetic disease is caused by their parents, carrying gene each of CF and having a 25% chance that their child will have CF. For patients with сystic аibrosis, ‘cross-infection’ between each other can pose serious death risks. CF patients have ‘bugs’ in their lungs that are harmless to people who do not have the condition, but it is easily transmitted from a CF patient to another. When there is more than 1 person with CF at one place, a distance of 6 feet (2 meters) at all times has to be between these patients. A distance of fewer than 6 feet can lead to germs interchanging, which can create an infection. No two patients are the same, therefore each ‘bug’ inside of the patient’s lungs is each uniquely different. When two CF patients meet, it increases the risk of the patients to develop infections from the different ‘bugs’ in each patient’s lungs. Some dangerous infections include B. Cepacia complex and pseudomonas aeruginosas.

Researches have shown that because of сystic аibrosis, they tend to suffer from depression. They are more likely to experience depression than people in the general population. Mainly, aspects of living with CF and how it has affected their life is the reason most CF patients and parents experience depression. Lives of CF patients can be very different from healthy children. CF patients need special food, treatments, and regular procedures like blood tests. Other than that, behavioural challenges accompanied by feelings are different than normal children. Viewing from the eyes of a CF patient, Katherine Scrievener, stated that she struggles not to feel restricted by the forever feeling of sadness that comes with having a life-shortening illness, сystic аibrosis. She struggles to feel happy for her friends who achieve their milestones. She struggles to relate to her peers. She struggles to relate to everyone. All of her struggles lead her to be lonely and isolated. However, connecting with the CF community online helped her in fighting the loneliness. One of the social networks such as Cystic Fibrosis Canada, a national charitable non-profit corporation which helps CF patients find one another and converse from video-chat, instant message, and online forums. As a non-profit corporation, they invest more in life-saving CF research and care. They are one of the top organizations who committed to finding a cure for сystic аibrosis (CF). They invested more than $261 million for leading research, innovations and care for patients with сystic аibrosis. As of today, they continue to fund leading research projects, fellowships and studentships to find a cure for сystic аibrosis. They provide social networks for CF patients to gain networks with other CF patients, without the boundary of 6 feet apart.

Nowadays, due to the evolution of technology, it is more accessible for CF patients to gain a network and communicate with other patients as well. Because they struggle to relate to normal children, interacting with other patients can allow themselves to feel less lonely, which can reduce the probability of them getting depression. Aside from communication with others, social networks can also be used as a source of information and support. Other than as a platform of social networks for CF patients, it could also be used for promoting patient engagement, facilitating access to information about health and services, and discussing research.

In my opinion, I support that CF patients use technology as a bridge between a patient to another, as support to other patients through donation and charities, and even as a source of information and researches. Other than being connected to the world, CF patients can express themselves and escape the restrictions that CF has blocked them from doing, which can decrease the probability of them to get depression. It helps them to be connected to other CF patients that experience mostly the same things they experience as well. Studies of 11 adolescents have shown that small support group has proven that 100% of them agree that these support groups made them feel connected to other teens with CF. Not only will they exchange their experiences or get along with each other, but also to support each other through these support groups that the internet has provided them with. This makes them feel that they aren’t alone, because other patients also feel the same way as well. Through these support systems, it can decrease the rate of depression through connections they gain on the internet. Patients may learn from each other’s experiences regarding CF, help prevent feelings of isolation, and also prevent the possibility of them even anxiety and depression from starting in the first place.

In conclusion, it is shown that CF patients tend to get depressed mostly because there are several restrictions regarding their sickness. Not only are they restricted to be less than 2 meters away from other CF patients, but it also limits their connections with other people, which can affect their social life with other people. Mainly, loneliness is an effect that patients experience since they cannot relate to anyone other than other patients. In addition to that, they aren’t able to connect with other patients as well. This may cause them to be more likely to experience depression.

References

1. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/
2. https://www.cff.org/Life-With-CF/Caring-for-a-Child-With-CF/Working-With-Your-Childs-School/When-There-s-More-Than-One-Person-With-CF-in-the-Same-School/
3. https://www.cysticfibrosis.org.uk/the-work-we-do/conference-and-meetings/cross-infection-at-events
4. https://www.thestar.com/life/health_wellness/2013/05/16/cystic_fibrosis_patients_cant_risk_health_by_meeting_in_person_but_now_have_online_hangout.html
5. https://www.cysticfibrosis.ca/
6. https://www.cff.org/Life-With-CF/Daily-Life/Emotional-Wellness/Depression-and-CF/
7. https://cysticfibrosisnewstoday.com/2017/07/05/cross-infection-danger-living-cystic-fibrosis/
8. https://www.cff.org/Living-with-CF/Emotional-Wellness/Depression-Anxiety-and-Cystic-Fibrosis-What-the-Guidelines-Mean-for-You.pdf
9. Quittner AL, Goldbeck L, Abbott J, Duff A, Lambrecht P, Solé A, Tiboshc MM, Brucefors AB, Yüksel H, Catastini P, Blackwell L, Barker D. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax. 2014;69:1090–1097. doi:10.1136/thoraxjnl-2014-205983
10. https://cysticfibrosisnewstoday.com/cystic-fibrosis-emotional-wellness/
11. https://www.cff.org/CF-Community-Blog/Posts/2015/A-Little-Less-Lonely/
12. https://openres.ersjournals.com/content/2/1/00015-2016
13. https://www.thestar.com/life/health_wellness/2013/05/16/cystic_fibrosis_patients_cant_risk_health_by_meeting_in_person_but_now_have_online_hangout.html
14. https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(15)00436-1.pdf
15. https://cysticfibrosisnewstoday.com/2017/10/03/danger-cross-infections-living-cystic-fibrosis
16. https://www.cfcanadahomecoming.com/
17. https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700

More than 30,000 people worldwide are living with Cystic Fibrosis. Cystic Fibrosis is a recessive genetic disease in which a mutation occurs in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7. There is a plethora of different mutations that occur, but 70% of mutations that cause cystic fibrosis is the delta f508 mutation. A common cause of cystic fibrosis involves deletion of a codon, 3 nucleotide bases. CFTR proteins resemble a chlorine channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The mutation causes a dysfunction of the salt and water balance, resultantly causing thick mucus and salt reduction through excessive sweating. Due to the absence of Cilia and therefore an absence of the process mucociliary clearance, there is a mucus build-up within the lungs. This makes it difficult to breathe, allows poor growth and may result in coughing up mucous.

Clustered Regularly Interspaced Short Palindromic Repeat, also known as CRISPR, is a technology that targets gene mutations in specific DNA to restore it completely. This consists of two components, the Cas9 protein, and the attached guide RNA. CRISPR-Cas9 are enzymes found in bacteria that control microbial immunity. The guide RNA recognizes and locates the mutation in the genome sequence. The Cas9 protein will cut the mutation out of the DNA and either modify, remove or replace the sequence from the DNA chain. The complex is programmable therefore proving to be a precise technology. It is through this process that scientists plan on curing genetic and immune diseases, and substantially improve the immune system.

Cystic Fibrosis, AKA CF, is a recessive genetic disease, therefore, to have CF, there is a requirement of two mutated genes from the parents. However, if there is only one mutated gene the person is classified as a carrier, this can be seen on this pedigree chart. The mutation in the delta f508 gene is caused by the deletion of a codon, three base pairs of the CFTR gene, leading to the loss of phenylalanine. In heterologous cells, defective processing of the DeltaF508 protein results in endoplasmic reticulum retention, proteolytic degradation, and absence of other conductances.

Since 1989 when scientists discovered this CFTR gene, they have been actively seeking ways to cure the various genetic mutations that occur. In the past, and even currently, people with CF have been taken over 50 medication tablets a day to control the disease’s reckless effect on their lungs and digestive system. However, as each CF patient is so individually different, it is hard to find one medication or cure to apply to them all. CF patients also have the option to receive lung transplantation, however, there is a small quantity of accessible lungs. Due to this, 15 in 58 people with CF have died while waiting for a lung transplant. However, successful lung transplants are the most effective intervention in terms of clinical improvement.

In a 2014 study, CRISPR Cas9 was discovered as a possible technology for adult animals. Yin et al. demonstrated that in changing only 6% of cells, CRISPR was curative to tyrosinemia, a single-gene mutation, hereditary condition. Now there has been progress to use CRISPR/Cas9 to cure immune and genetic diseases within people.

One of the major benefits of CRISPR is the efficiency and simplicity of the process. The recorded reasons as to why this is beneficial is due to the embryotic application, the reduction of time required to modify target genes, improvement of the guide RNA replacement processes and also, how the flexibility of procedures has been increased due to the enhancement of experimental conditions.

If CRISPR is to be used therapeutically, it will have to overcome some major obstacles when referring to the process. CRISPR has the potential to target the wrong DNA cells which will result in severe harm to a person. In 2016, AJ Stem Cells state that before human clinical trials begin, researchers must overcome the obstacles of – “the reaction of the human immune system, efficient modes of delivery, determining that a correct copy of DNA is inserted into the sequence, safeguarding against Cas9 proteins cutting at incorrect locations and understanding and controlling off-target effects” (AJ Stem Cells, 2016).

These obstacles are being evaluated and researchers are finding a way to get around this. For example, to reduce the risk of off-target effects, Kleinstiver affirms that there are strategies in place to improve the algorithms to “design guide RNA’s and engineering Cas9 enzymes with higher fidelity and specificity” (Kleinstiver et al., 2016).

The Society of Thoracic Surgeons points out that CRISPR has revolutionized laboratory science. Although there are high risks and apparent obstacles, the has been significant progress over the past 30 years. When looking forward, there are controversial discussions as to whether genome modification technology should be used to edit the human body. A lot of genetic diseases prevent and disrupt the development of organs. As CRISPR has granted the ability to replace genomes and cure genetic diseases, it would be beneficial to edit the genomes when the human is in embryonic form as this would prevent the disruption of development. This is called germline engineering; additionally, this will prevent the inheritance in future generations. However, an ethical dilemma arises when considering CRISPR Cas9 on embryos. Adults can give full consent, whereas embryos cannot provide informed consent. Patients who have incurable diseases are often willing to participate in clinical trials as they live a quality-compromised life and are presented with no alternative treatments. A consideration that must be made with the embryotic application is the stage of development of which the embryo should be operated on.

The commencement of human trials in CRISPR can lead to the concern of further trials on embryos then into ‘designer babies’. The term ‘designer babies’ is when one can pick and choose exactly what traits or characteristics, they want their child to have. This removes the naturality of conception and birth, which raises ethical issues.

The cost of CRISPR Cas9 ranges from $500,000 to $1.5 million. This raises the question of whether the technology is worth funding. If the obstacles are overcome and CRISPR/Cas9 is applied to humans, there will have to be strict lines drawn to ensure that the technological processes are still ethical. For example, CRISPR needs funding but should only be used for curing diseases and not to advance the normal body. Laws will have to be made by the government to assess what is in measurable terms of this technology.

Furthermore, the respiratory, digestive, reproductive and sweat glands are most affected by cystic fibrosis. There are many types of treatments that can aid these systems. The nervous system and the brain are least affected, making a child’s ability to learn not adjusted by cystic fibrosis.

While the brain is typically not affected by those with cystic fibrosis, the lives of these individuals can become drastically different from those of healthy people. A high maintenance lifestyle typically becomes more prevalent in a child with cystic fibrosis as they can require feeding, treatments, and procedures like blood tests and more. When the disease becomes more severe, there can be behavioral challenges and other psychological difficulties involved. As they become teenagers, frustration may arise as they are in the hospital often to care for their treatments. Body image is often a problem for patients growing up with this disease as puberty and menstruation is typically delayed a few years.

It is common for children with this disease to attain feelings of depression and anxiety due to the lack of total control of their health. Patricia Silva, PhD, is the author of ‘Cystic Fibrosis and Emotional Wellness’. She finds that anxiety is “one of the most common emotional issues faced by these patients”. “This is related to daily treatments, remembering to take medications, missing out on things they want to do, and being hospitalized for periods of time”. Along with this, patients of CF are very likely to suffer from depression and feelings of hopelessness.

Despite all of this, one can seek emotional wellbeing by recognizing the signs and realizing that they are not alone. Patricia Silva states that “patients and loved ones can seek psychological help with specialists or with support groups, which are common not only in associations and organizations like the Cystic Fibrosis Foundation, but also among specialized medical centers”. A child life specialist may be able to recommend patients and their families to these foundations as a way for them to gain support.

Currently, there is no direct cur for cystic fibrosis. There are many treatments for a CF patient. These treatments are to prevent infections and while trying to keep the airways clear in order to live as comfortably as possible. Moreover, maintaining adequate nutrition is also important for a CF patient as they do commonly develop CF related diabetes. These treatments can affect their everyday lifestyle as they can be in the hospital more frequently. CF patients and their families work with many healthcare professionals in order to make their treatment processes easier and more effective.

A child life specialist may intervene with a cystic fibrosis patient in many ways. First of all, there are many books that can be given to the patient, according to their developmental level. There is ‘Cystic Fibrosis and You’, by Emilie Sasso. According to the author, this book was written to encourage children with CF to maintain a positive life and accomplish their dreams. For older CF patients, there is ‘Cystic Fibrosis: The Ultimate Team Guide’, by Melanie Ann Apel. This book is a little more serious by explaining procedures while interviewing other teens with CF on how they live their life to the fullest. The overall goal for a child life specialist is to offer opportunities to play and interact with others in an emotionally safe environment.

Usually, infants will visit the CF clinic everyone to three months during the first year of life and begin more frequent visits around the age of two. Kirsten M. Black, a graduate student in child life administration at the University of La Verne, wrote ‘Child Life in the Cystic Fibrosis Center’, a handbook on how to handle a patient with CF and their family. She goes on to clarify how CF can be defined to a preschool age sibling by explaining it in an age appropriate manner. She states that “parents need to be educated on the importance of enzyme replacement therapy” and much more. Pancreatic enzyme replacement therapy (PERT) can be defined as the utilization of medications that contain enzymes to replace what the pancreas is no longer releasing in order to maintain proper digestion. According to Pancreatic Enzyme Replacement Therapy use in infants with cystic fibrosis diagnosed by newborn screening, a study conducted by pediatricians, “improved growth early in life is associated with better clinical outcomes later in life” determining PERT as an “important therapeutic recommendation”. At the stage of PERT (infancy), the parent is more involved than the patient. The child life specialist may intervene in this situation by providing the parents with informational booklets about PERT. In addition, the child life specialist can demonstrate to the parents how to open the capsules and feed it to their baby.

As children reach preschool age, they begin pulmonary function tests (PFT’s) and start to learn to swallow pills (enzymes and vitamins). This is when the child life specialist can start to teach on how to master swallowing pills. The child life specialist can engage in pretend play with the patient and their dolls and pretend to feed them fake pills. This familiarizes the child the with aspect of swallowing pills. Another way to familiarize the patient with pill swallowing is by playing “hungry hungry hippo”, according to Black. The author goes on to state an example of this as referring to the balls as “enzymes” and asking the child if “they think they can swallow as many enzymes as the hippos in the game”. The parents can also play a role in this learning by reinforcing pill swallowing at home.

As a CF patient approaches the school age, psychosocial difficulties may be developed sa they are adjusting to new routines while entering school. The child may gain more responsibilities of self-care as they are maturing and able to comprehend their disease and the purpose of their treatments a little more. Respiratory therapy, often known as airway cleaning, becomes more prevalent in their life at this age. A child life specialist can plan for intervention in order to inform the school ager on airway cleaning in many different ways. One way is that they can utilize a straw painting exercise. The child life specialist will utilize a straw to blow bubbles into paint while touching paper to the bubbles in order to make prints on it. The purpose of this activity is to introduce respiratory clearance techniques in a fun way. The child life specialist then continues to explain how breathing into a straw against thick paint is “creating a small backflow of air that pushes back into your lungs and helps to open airways” making it easier for mucus to be cleared. Furthermore, this type of education on a school ager allows the child life specialist to incorporate play while teaching them about necessary techniques in an age appropriate manner.

Along with adolescence comes the topics of independence, sexuality and body image. In addition, they learn to take charge of their own airway clearance and the management of enzymes and digestion at this stage. Adolescence also often brings along the challenge of CF-Related Diabetes (CFRD). A lot of patients at this age experience their first hospitalization during this period while having their first experience with intravenous antibiotic therapy. The child life specialist can work with the patient in the Child Life Center to discuss upcoming hospitalization and the need for antibiotic therapy and its implementation. Once the line becomes in place, the child life specialist can engage the patient in movement by playing an active Wii or Xbox game while discussing perceived and real restrictions of having this line in place.

Family centered care can be defined as the establishment of relationships with patients and their families in order to recognize the importance of family roles in health care as an effective influence on the patient’s treatments. In the research known as, ‘Patient- and Family-Centered Care: It’s Not Just for Pediatrics Anymore’, Aaron Clay, RN and Bridge Parsh, RN, MSN, EdD, emphasize that hospitals where family centered care is part of the organizational culture find “not only that patient, family, and staff satisfaction ratings significantly increase, but also that patients’ health outcomes improve”. ‘Practice applications of research. Perceived needs of parents of critically ill infants in a neonatal intensive care unit (NICU)’ is another research on the importance of family centered care done by Kylie Ward. The author found that “answering parents’ questions honestly, actively listening to their fears and expectations, assuring parents that their infant is receiving the best care possible” and “demonstrating a genuine concern for the whole family” decreased the anxiety of parents. Family centered care is a large portion of the job of a child life specialist as their aim is to decrease trauma while maintaining development in the hospital.

Introduction

This report contains information on the disease cystic fibrosis and how people with it manage their life. The inherited disease cystic fibrosis is a condition that causes a thick mucus to build up in the lungs causing decreased lung function making anyone who has this condition life increasingly difficult keeping up with medications that can increase their quality of life.

How the respiratory system works normally

The respiratory system is one of the systems that help keep us alive. When we breathe in we go through inspiration this is where the muscles in our chest under the ribs (intercostal muscles) pull the ribs up and out letting the diaphragm flatten the abdomen by contracting causing the pressure in the lungs to decrease letting air in. after the air is inhaled the lungs then go through expiration to let the air (carbon dioxide) out causing the lung pressure to increase. The normal lung working capacity is round about 70% making tasks like running and walking such easy tasks. Although we can still get chest infections during the winter months in mst cases its not as serious as a person with cystic fibrosis as our immune systems are able to withstand much more than a person with cystic fibrosis is able to.

The effects of cystic fibrosis on the body

Cystic fibrosis primarily affects the lungs. People with cystic fibrosis have a life expectancy of around 37 years but it is constantly going up due to scientists constand studies and research. Many complications can be side effects of cystic fibrosis which can make anyone living with this disease life increasingly hard to manage. Living with cystic fibrosis can have an increasingly higher risk of having osteoporosis, liver problems, sinus infections and are also more prone to having diabetes. Among all of the other complications people with cystic fibrosis can contract chest infections that can be life threatening and could weaken their lungs further. In most cases people with cystic fibrosis need to have a lung transplant as their lungs start to weaken so much that their lungs can’t support them anymore.

Diagnosis and care

Cystic fibrosis can be found pretty early on doctors often perform a heel prick on newborn babies to determine if the baby has the genetic disease although this heel prick cannot detect all forms of cystic fibrosis. There is not yet a cure for cystic fibrosis but it can be managed children and adults are advised to eat a diet high in calories and vitamins but overall just a healthy balanced diet to help them grow. People with cystic fibrosis often struggle to breath their lungs are coated in a thick sticky mucus to help clear this they can often attend physical therapy or use a special type of vest to break up the mucus called an afflovest so that they can cough up this mucus. There is also medication that can help prevent these chest infections helping to keep them out of hospital. Taking part in aerobic exercises that cause you to breathe harder can also help breakup the mucus. The only downside to this form of exercise is it causes you to sweat causing you to lose salt so doctors may often recommend that you have a diet high in salt. Doctors can prescribe medicines such as mucus-thinning medicines, antibiotics and anti-inflammatories that help to thin the mucus, help open up the airways and reduce swelling that can occur.

Summary

Overall cystic fibrosis can be a difficult disease to manage but it can be done although people with cystic fibrosis have a decreased life expectancy they still try to make the most of it despite the multiple hospital visits and the tests they have to go through.

Abstract

Cystic fibrosis (CF) is a multisystem disorder that originates in the respiratory system of individuals. It is caused by a malfunction of the cystic fibrosis transmembrane receptor protein (CFTR). Improved understanding of the CFTR gene has opened doors to better understand the disease itself through research and experimental procedures. Understanding the pathophysiology of the CFTR gene itself has also raised questions about the potential benefits of gene therapy in cystic fibrosis patients. Treatment for cystic fibrosis is prioritized on the improvement of life-threatening symptoms of the disease and the elimination of the things causing these symptoms. Overall, treatments for cystic fibrosis are complex and there are several gaps in research evidence. The purpose of this review study is to explore the pathophysiology of cystic fibrosis presented in scientific literatures and provide recent information on the diagnosis and treatment therapies.

Introduction:

Cystic fibrosis (CF) is a genetic disease that affects the respiratory system, and consequentially the digestive, reproductive, immune, and endocrine systems of the individuals effected. CF is caused by an inherited mutation in the cystic fibrosis transmembrane regulator (CFTR) gene (Donnelley & Parsons, 2018). As a recessive genetic disorder, CF is inherited when two carrier parents (who have one normal gene, and one gene with the mutation) each pass the abnormal CFTR gene to their child. The most common mutation is a deletion of phenylalanine at position 508 (ΔF508), which accounts for 70% of cases. (Nicholson & Sheppard, 2014). Cystic fibrosis is a persistent, life threatening disease that causes an accumulation of mucous in the lungs, leading to chronic symptoms and most commonly pulmonary disease (Cystic Fibrosis Overview, 2019). The thick and sticky mucous produced in the lungs of individuals with CF harbors bacteria and makes it extremely difficult to breath. This life-threatening illness is terminal; with most patients living until around age forty (Donnelley & Parsons, 2018). Though there is no cure for this disease, research advances within the last decade have provided further understanding of the disease and the improved development of therapeutic approaches in order to manage cystic fibrosis and its associated symptoms.

Cystic fibrosis effects at least 30,000 people in the United States and between 900 and 1,000 new cases are diagnosed every year. One in 29 people of Caucasian ancestry is an unaffected carrier (heterozygous) of the CF gene mutation. In the United States, cystic fibrosis occurs at a rate of 1 in 3,400 births, with most cases associated with Caucasian racial background. Most individuals with cystic fibrosis were diagnoses by five months of age; however, the average age of diagnosis was five years. Many are not even diagnosed until adulthood (Cystic Fibrosis, 2014).

Etiology

A mutation, or alteration, in the host genome affects the production of certain proteins needed for important biological functions. Almost 2,000 mutations in the CFTR gene have been found to cause cystic fibrosis (Hodges & Conlon, 2019). When there is a mutation in the CFTR gene of individuals, the production of the CFTR protein may be affected. Individuals that have cystic fibrosis disease possess these mutations in the CFTR gene. These mutations either result in the complete absence of, or reduction of the CFTR protein, or an incorrect protein with the wrong configuration (Gene Therapy for Cystic Fibrosis, 2019). The ultimate role of the CFTR gene is to maintain the flow of salt (sodium and chloride) and water across the cells that line the respiratory, digestive, and reproductive tracts. A mutation in this gene therefore decreases the flow of salts through the epithelia of multiple organs, including the lungs, sweat glands, vas deferens, liver, and intestines. (Pranke et al., 2019) The decreased flow of salt ions results in a reduction of water in the fluid lining the airways. The lack of water production in these airways drives the accumulation of abnormally thick and sticky mucous that underlies chronic lung inflammation and recurrent bacterial infections, leading to continuous lung deterioration. (Pranke et al., 2019). The inactive flow of water and salt ions allows for increased inflammation and thus inflammatory response. The neutrophils secreted by the body’s immune system further enhances inflammation because they produce elastase and proinflammatory cytokines (Nichols and Chmiel, 2015). This vicious cycle of airway obstruction, inflammation, and persistent infection leads to decrease in lung function, eventually leading to respiratory failure and death. Clogged mucus secretions can lead to additional problems in other organ systems in the body as well (Cystic Fibrosis, 2014).

Pathophysiology (symptoms)

There are various symptoms associated with cystic fibrosis disease. Among the most common and consequentially the most life-threatening of symptoms are those associated with the respiratory system, ultimately leading to the individual’s inability to breath. This is a result of damaged airways, or bronchiectasis, which makes it difficult for the transfer of air in and out of the lungs and clear the mucous from the airways. The thickened mucous provides an ideal breeding ground for bacteria and fungi which could cause additional infections such as: bronchitis, sinus infections, or pneumonia. Patients with more progressive forms of cystic fibrosis have hemoptysis, or coughing up blood. This happens due to the thinning of the airway walls over time. Other respiratory associated symptoms include pneumothorax which involves chest pain and breathlessness, and respiratory failure, which happens as a result of severe damage to the lung tissues that hinders the function of the lungs (Cystic Fibrosis, 2019).

Cystic fibrosis also causes digestive system complications such as: nutritional deficiencies, diabetes, blocked bile duct, intestinal obstructions, and distal intestinal obstruction syndrome (DIOS). Nutritional deficiencies happen as a result of thickened mucous preventing the transfer of digestive enzymes from pancreas to the intestines; this inhibits the body’s ability to absorb protein, fats, and some vitamins. Many CF patients also develop diabetes because the pancreas is unable to produce insulin—the hormone necessary to use sugar. Blocked bile ducts prevent the transfer of bile from the liver to the gallbladder, leading to liver problems and sometimes gallstones. That malfunctions of particular components of the digestive system could lead to even more complication in and, in later stages of cystic fibrosis, organ failure. (Cystic Fibrosis, 2019).

Treatments

Most CF patients die from infection present within the lower respiratory tract due to the accumulation of harmful bacteria within the viscous mucous in the lungs. The thickened mucosal lining of the airways harbors pathogens such as Staphylococcus aureaus, Haemophilus influenzae, and Pseudomonas aeruginosa. (Sheppard & Nicholson, 2014) The resulting immune response generated by the body to fight the infections imposed by these pathogens ultimately leads to pulmonary disease due to the lung damage caused by the increased inflammatory response.

Antimicrobial Treatments:

Several studies have been conducted to eradicate the detrimental side effects of bacterial infections on CF patients in an attempt to treat the symptoms of the disease and increase lifespan by slowing or eliminating pulmonary disease. One of the main causes of reoccurring pulmonary infections and the resulting life-threatening lung conditions in CF patients is caused by the bacteria Staphylococcus aureus; within the first three years of life. (Ranzenbacher et al., 2019). Two strains of this bacterium block the respiratory pathways of infected individuals: methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA). The most detrimental of these strains is MRSA considering the difficulty in treating the resulting infection with antibiotics. (Ranzenbacher et al., 2019).

In an attempt to eradicate MRSA and MSSA in CF patients, studies were conducted analyzing the effect of S. aureus colonization in the airways of CF patients and the different procedures for antimicrobial treatment. One specific study focused on the long-term antibiotics, rifampicin and fucidin in the attempt to eradicate the MRSA and MSSA. Eradication proved successful in patients exhibiting intermittent (less than 50 percent) bacterial colonization. With this, the data showed that the process of eradication of S. aureus in particular can improve patients most in early stages of CF when the percent of S. aureus colonization is lower than that of patients possessing a more progressed form of CF. (Esposito et al., 2019).

Apart from Staphylococcus aureus infection, Pseudomonas aeruginosa is another life-threatening bacterium that resides in the respiratory systems of cystic fibrosis patients. P. aeruginosa is noted as the major cause of mortality in CF patients. The gram-negative bacterium possesses virulence factors that secrete toxins for overcoming immune response produces by the host. (Bhagirath et al., 2016).

In patients with CF, their immune systems are compromised, making it an especially favorable environment for pathogens like P. aeruginosa. With this, there have been few experimental attempts to eradicated P. aeruginosa in CF patients. A 2014 study cultured the respiratory microbiomes of 279 CF patients, several patients exhibited the eradication or the slowed growth of P. aeruginosa after administration of several antibiotics and additional treatment methods (Kenny et al., 2014). These procedures are termed antibiotic eradication therapy (AET). The use of aggressive AET proved successful in the majority of adults exhibiting first-time P. aeruginosa infection (Kenny et al., 2014). Ultimately, this is important because the number of patients with CF entering adult care with no history of P. aeruginosa infection is increasing; therefore, these patients have an increased need for AET in order to help prevent chronic infections produced by P. aeruginosa and the resulting progression of lung damage and the disease in general.

Gene Therapy:

Scientists are exploring several strategies concerning gene therapy in patients with cystic fibrosis. With advancing technologies, the mechanism of gene therapy has become more achievable with new methods for genome editing such as Zinc-finger, CRISPER, and TALENs (Vargas et al., 2016). Gene therapy is the process by which the correct gene is incorporated into the host genome in an attempt to allow the host to construct more normal copies of the wild-type gene. In this case, the mutated form of CFTR gene would coexist with the normal CFTR gene, and the presence of the normal gene relocates to the epithelial cell layer in the airways with the goal of replacing the mutated gene and expressing the functional CFTR protein (Gene Therapy for Cystic Fibrosis, 2019). Although gene therapy has potential to make a significant impact in the lives of individuals with CF and possibly cure the disease as a whole, there are several limitations associated with gene therapy. First, determining the correct and most relevant plasmid DNA molecule model is important. Second, natural barriers such as mucus, immune responses, and intracellular limitations inhibit gene transfer into the lungs. Finally, gene therapy would need to be administered several times throughout the lifetime of the individual due to the fact that the epithelium lining the airways is constantly regenerating. (Pranke et al., 2019). Another disadvantage of gene therapy in CF patients is that this strategy only works in the specific cells that receive the therapy. This being said, gene therapy could be used to treat the lungs, but it will not help the cells in other organ systems throughout the body that are affected by CF, such as the digestive system (Gene Therapy for Cystic Fibrosis, 2019). Taking these disadvantages into consideration, the selection of the appropriate method of gene therapy is essential for success of the treatment. There are three types of gene therapies that have potential to treat cystic fibrosis: integrating gene therapy, non-integrating gene therapy, and RNA therapy (Gene Therapy for Cystic Fibrosis, 2019).

Integrating gene therapy involves the incorporation of DNA containing the corrected CTFR gene into the host genome. This is a permanent integration which could be beneficial in that the patient may only need to receive the therapy a small number of times; however, there is little control in where exactly the gene will be inserted into the host genome associated with this therapy type (Gene Therapy for Cystic Fibrosis, 2019). There are several forms of integrating gene therapy that have been used in the treatment of patients with certain cancers, however, research is still underway in order to determine a beneficial effect of this type of gene therapies in CF patients. Recent studies have examined lentiviral vectors and non-viral vectors as integrating vectors into CF patient genomes (Cooney et al., 2018).

Non-integrating gene therapy involves the incorporation of the correct copy of the CTFR gene into the host genome, without disrupting the genome itself. The gene of interest is simply placed within the genetic information of the individual, but still remains separate from the individual. This form of gene therapy can be beneficial concerning the limited side effects that occur. Though, a disadvantage to this type of therapy is that is not permanent because the new CTFR is not in direct correlation with the rest of the host genome. For this reason, non-integrating gene therapy needs to be administered several times during treatment in order to be beneficial.

In recent years, use of several different types of viral vectors are of high interest in the research of gene therapy for cystic fibrosis patients. A study published in March of 2019 examined the use of lentiviral vectors in the potential prevention of cystic fibrosis lung disease. The lentiviral vector is a type of retrovirus that can transduce in dividing and non-dividing cells. Successful therapies using this type of vector would be beneficial in CF patients especially because they can provide long-term transgene expression. In the particular study in 2019, the lentivirus was evaluated based on successful platforms that vector produced in earlier studies with HIV, FIV, EIAV, and SIV (Marquez Loza et al., 2019). Furthermore, a study in 2016 worked to identify a variety of pre-clinical trial components associated with the lentiviral vectors: mapped integration sites, characterized transduced cell types, assessed acute toxicity, determined the effects of pre-existing immunity on transduction efficiency and toxicity, assessed CFTR function of our lead vector, and quantified vector stability in delivery devices suitable for a first-in-man trial. After careful evaluation of all these necessary components for gene therapy, the study supported the proposed use of the particular lentiviral vector in a future first-in-man clinical trial (Alton et al., 2016).

Cystic Fibrosis is a detrimental disease that comes with numerous complications associated with several different organ systems within the human body. The etiology, pathophysiology, and treatments provide a solid foundation to the understanding of Cystic Fibrosis. As a genetic disease, there is no cure; however, research is directed toward therapies that target the symptoms of the disorder in order to make the disease more manageable for individuals with CF. With the development of new genetic and biomedical technologies, future direction aims to use gene therapy as a means for treating the disease. There is still a lot that is unknown about gene therapy, and though there is no cure for cystic fibrosis, there is hope that developing research will eventually provide answers to fix the mutated CFTR gene permanently. The ultimate goal is to change CF from cystic fibrosis to cure found.

References

1. Alton, E. W., Beekman, J. M., Boyd, A. C., Brand, J., Carlon, M. S., Connolly, M. M., … Zhu, J. (2017). Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax, 72(2), 137–147. doi:10.1136/thoraxjnl-2016-208406
2. Bhagirath, A. Y., Li, Y., Somayajula, D., Dadashi, M., Badr, S., & Duan, K. (2016). Cystic fibrosis lung environment and Pseudomonas aeruginosa infection. BMC pulmonary medicine, 16(1), 174. doi:10.1186/s12890-016-0339-5
3. Cooney, A. L., P.l B. McCray, Jr and Patrick L. Sinn (August 24th 2015). Integrating Viral and Nonviral Vectors for Cystic Fibrosis Gene Therapy in the Airways, Cystic Fibrosis in the Light of New Research, Dennis Wat, IntechOpen, DOI: 10.5772/60977
4. Cooney, A. L., McCray, P. B., Jr, & Sinn, P. L. (2018). Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward. Genes, 9(11), 538. doi:10.3390/genes9110538
5. Cystic Fibrosis. (2014) American Thoracic Society. Retrieved from https://www.th oracic.org/pat ients /lung-disease-week/2014/cystic-fibrosis-week/general-info.php
6. Cystic Fibrosis. (2019). Mayo Clinic. Retrieved from https://www.mayoclinic.org/diseases- conditions /cystic-fibrosis/symptoms-causes/syc-20353700
7. Cystic Fibrosis Overview. (2019). Stanford Children’s Health. Retrieved from
8. https://www.stanfordchildrens.org/en/topic/default?id=cystic-fibrosis-overview-90- P09526
9. Donnelley, M. and D. W. Parsons (2018) Gene Therapy for Cystic Fibrosis Lung Disease: Overcoming the Barriers to Translation to the Clinic. Frontiers in Pharmacology. 9:1381. doi: 10.3389/fphar.2018.01381
10. Esposito S, Pennoni G, Mencarini V, Palladino N, Peccini L and Principi N (2019) Antimicrobial Treatment of Staphylococcus aureus in Patients With Cystic Fibrosis. Frontiers in Pharmacology. 10:849. doi: 10.3389/fphar.2019.00849
11. Gene Therapy for Cystic Fibrosis. (2019). Cystic Fibrosis Foundation. Retrieved from https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Gene- Therapy-for-Cystic-Fibrosis/
12. Hodges, C. A., & Conlon, R. A. (2018). Delivering on the promise of gene editing for cystic fibrosis. Genes & diseases, 6(2), 97–108. doi: 10.1016/j.gendis.2018.11.005
13. Kenny SL, Shaw TD, Downey DG, et al. Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis. BMJ Open Respiratory Research 2014;1:e000021. doi: 10.1136/bmjresp- 2014-000021
14. Marquez Loza, L. I., Yuen, E. C., & McCray, P. B., Jr (2019). Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease. Genes, 10(3), 218. doi:10.3390/genes10030218
15. Nichols, D. P., J. F. Chmiel. (2015). Inflammation and Its Genesis in Cystic Fibrosis. Pediatric Pulmonology. 50:S39-S56. Doi: 10.1002/ppul.23242
16. Pranke I, Golec A, Hinzpeter A, Edelman A and Sermet-Gaudelus I (2019) Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine. Frontiers in Pharmacology. 10:121. doi: 10.3389/fphar.2019.00121
17. Ranzenbacher, L., Y. Song, A. Merchant, and P. G. Middleton. (2019). Intermittent Colonization with Methicillin-Resistnant Staphylococcus aureus Can Be Eradicated from the Airways of Adults with Cystic Fibrosis. Antibiotics 8, no. 3: 113
18. Vargas, J.E., Chicaybam, L., Stein, R.T. et al. Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives. J Transl Med 14, 288 (2016) doi:10.1186/s12967-016-1047-x

Abstract

The genetic disorder that I choose was Cystic Fibrosis, also known as CF. CF is caused by a change and/or mutation in the cystic fibrosis transmembrane conductance regulator also known as CFTR gene. People who have CF inherit two copies of the CF gene, one gene from each parent. The CFTR gene controls the flow of salt and fluids in and out of your cells. Since the CFTR gene controls if it does not as it was meant to, then sticky mucus builds up in the body. Cystic Fibrosis affects mainly the lungs and the digestive system. People who have CF are prone to contracting lung infections. There is no cure for Cystic Fibrosis at the current time.

History

The earliest record of Cystic Fibrosis is in 1983 from an American pathologist Dr. Dorothy Andersen who provided the first description of the disorder in the medical literature. Dr. Dorothy Andersen called the disease “cystic fibrosis of the pancreas” based on the children who died of malnutrition. In 1948, Dr. Paul di Sant’ Agnese found that the sweat of children who had CF abnormally high salt concentration. In 1955, The Cystic Fibrosis Foundation was formed by a group of concerned parents who were determined to save the lives of their children. The predicted age of survival changed from 10 in 1962, 16 in 1970, and in 1980 the age was 18. In 1963, the US CF Foundation wrote a guide for diagnosing cystic fibrosis. The medical centers devoted to CF went from two to more than 100 through 1961-1978. In 1989, a team of scientists discovered the defective cystic fibrosis transmembrane conductance regulator (CFTR) and open the door to understanding the disease at the most basic level, and the predicted age of survival changed to 19. In 1993 and 1997, the FDA approved of Pulmozyme and TOBI two different antibiotics designed for CF. These helped reduce hospital stays and improve lung function. In 2000, the median age improved to 32 and in 2004, studies and the University of North Carolina found that hypertonic saline helps clear CF mucus. One of the first oral drugs to work on a cellar level (VX-770) was found in 2006. The first march was held in 2007 to educate elected officials about the need for continued funding for NIH, the FDA, and other drug development and research programs. In 2008 phase two studies of the oral compound VX-770 showed an increase in lung function and improvements in overall health and well-being, proving that it is possible to treat the root cause of CF. The foundation raised $175 million through the milestones campaign in 2010. The money that was raised was used to fund research projects, buy better equipment, etc. Throughout 2011- 2013, phase 3 clinical trials of ivacaftor (VX-770) show profound results and the foundation a new drug application was submitted under the trade name Kalydeco, the FDA approved of ivacaftor/Kalydeco for a small group of people 6 and older, and two large international phase 3 trails of ivacaftor. In 2016, the FDA approved the ivacaftor for children with CF ages 6 to 11 who have two copies of F508del mutation (one of the many types of CF mutations). This made nearly 11,000 in the US eligible for the treatment. In 2018 the foundation maintains a robust pipeline of potential therapies that target the disease at every angle.

Symptoms

The most common symptoms of Cystic Fibrosis are very salty-tasting skin, persistent coughing at times without phlegm, wheezing, coughing blood, frequent lung infections such as pneumonia or bronchitis, greasy, bulky stools or difficulty with bowel movements, infertility especially in males, and poor weight gain in spite of excessive appetite. More extreme symptoms are pancreatitis, or inflammation of the pancreas, diabetes, nasal polyps or small fleshy growths found in the nose, jaundice/ yellow skin, and Pneumothorax which collects air in the space that separates the lungs from the chest wall. This condition can cause chest pain and breathlessness. If you experience most of the common symptoms and at least two of the more extreme symptoms, please see your local doctor to see if you or your child have Cystic Fibrosis.

Causes

Some causes of cystic fibrosis are family history and race. Since Cystic Fibrosis is a genetic disorder you are born with CF. People with CF get CF from their parents. To get it you must have two copies of the defective CF gene. One copy from each parent, so both parents must have at least one copy of the defective gene. One of the causes of Cystic Fibrosis is family history because it is an inherited disorder, so it runs in families. Race is another type pf cause even though it occurs in all races, it is most common in white people of Northern European ancestry. Cystic Fibrosis is one of the most common genetic disorders and 1 in 2,5000-3,500 Caucasian-Americans, 1 in 4,000-10,000 Hispanic-Americans, 1 in 15,000-20,000 African Americans, and 1 in 100,000 Asian-Americans. Also, CF cannot transmitted.

Treatments

There are currently many treatments to help slow down the process CF. One treatment is antibiotics to treat and prevent lung infections, or anti-inflammatory medications to help with swelling in the airways of your lungs. They include ibuprofen and corticosteroids.

It is one of the most common genetic disorders in Caucasians. A defective gene and its protein product cause the body to produce a very thick mucus that clogs the lungs and can lead to life-threatening infections. It also obstructs the pancreas and stops natural enzymes from helping the body to break down and absorb food. It’s caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). (Davies, Alton and Bush, 2007) Ireland has the highest incidence of CF in the world. Symptoms of CF include very salty- tasting skin, a persistent cough, frequent lung infections, wheezing or shortness of breath, poor growth or weight gain in spite of a good appetite and frequent greasy, bulky stools or difficulty in bowel movements. (Byrne, Heffernan, & Tallon, 2019)

Mucosal tissue represents the site of infection in human diseases. Mucins are glycoprotein constituents on mucous. Mucins give mucous its gel like structure. Gel-forming mucins are the primary macromolecular components of airway mucus, they assist in airway clearance by mucociliary transport. In CF altered mucus properties impair mucociliary transport. The main gel-forming mucins in the airways are MUC5B and MUC5AC. (Lillehoj, 2017)

The key bacterial agent of CF lung infection is Pseudomonas aeruginosa. P. aeruginosa is the most important pathogen in progressive and severe CF lung disease. Patients are often exposed to this in hospitals and other healthcare settings. P. aeruginosa infections tend to set in after the lung airways are clogged by mucoid secretions. This reduces mucociliary clearance of inhaled microbes, this leads to the formation of bacterial biofilms with mucoid layers as their habitat. Once biofilms are formed, inflammation occurs, in some cases this leads to chronic infection. (Silva, 2019)

P. aeruginosa is a common pathogen found in CF. This is primarily due to the overabundance of mucus in CF airways which causes the perfect environment for P. aeruginosa to thrive in. The mucins found in CF airways are also heavily sialylated which allows P. aeruginosa to bind to them in the first place. The level of glycosylation of mucins directly correlates with the severity of infection in CF patients.(Jeffries et al., 2016)

Main Body

Cystic Fibrosis

Cystic Fibrosis is the most common life limiting autosomal recessive condition in Caucasians. Cystic fibrosis is a complex multi system disease. It affects the lungs, liver, pancreas, intestine, sinuses, bones and the male reproductive tract, however the majority of morbidity and mortality is associated with respiratory disease. Early detection of CF is vital. Improved diagnosis and symptomatic treatment have improved both the health and life span of people suffering with this disease. (Naehrig, Chao and Naehrlich, 2017) Improved diagnosis and symptomatic treatment have improved the health and survival prospects in CF patients. In the 1950s, the average life span of a person with CF was only a few months. Today, because of improved diagnosis and treatments the average life span has increased to 40 years. New-born screening detects cystic fibrosis. (Naehrig, Chao and Naehrlich, 2017)

Gene mutations in Cystic Fibrosis

CF is caused by a mutation in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Conductance is the ability of fluid to pass through the cell membrane. (Antoniou, 2016). The CFTR gene is located on the long arm of chromosome 7. Its main function is to regulate the movement of chloride, it’s also involved in sodium bicarbonate and water transport. A dysfunctional CFTR protein in the airway epithelial will cause the chloride secretion to become impaired. Increased sodium and water reabsorption combined with a reduction in chloride secretion compromises mucociliary clearance efficiency, which is the first line of defense in the respiratory system against pathogens. (Elborn and Vallieres, 2014)

A mutation in both copies of the gene is necessary in order for the disease to be present. The patient must inherit two copies of the CFTR gene that contains the mutation, one copy from each parent. Therefor each parent will either have Cystic fibrosis or they will be a carrier of the CFTR gene mutation.

In those without the mutation, the CFTR protein is produced normally, it reaches the cell surface and becomes an open channel for chloride ions to pass through. There has been over 1700 mutations in the CFTR gene identified, some are common while others are only found in a few people. The most common mutation of the CFTR gene is the Delta F508 mutation. This mutation results in the misfolding of the CFTR protein, which prevents it from moving to the cell surface. The mutant CFTR protein needs a corrector drug to boost it to the surface, it also requires a doorman drug to open the channel so that chloride ions can pass through. Another mutation, which is less common, is the G551D mutation. This differs to the delta F508 mutation as the CTFR protein is created and moves to the cell surface, however the channel does not open properly, and chloride ions cannot pass through.(Meng et al., 2017)

Figure 1 CFTR mutations (Lopes-Pacheco, 2016)

General Role of Mucins in Infection

Mucus has a gel like property which depends primarily on its content of mucins. Mucin genes encode the protein backbone of mucins. There are currently 20 mucin genes that encode the backbone of mucin proteins, 16 of these mucin genes have been identified in the airways. Mucus can be altered by primary mucus disorders, infections, some genetic abnormalities and drugs. Disease related alterations in posttranslational modification of mucins may contribute to the pathology of Cystic Fibrosis. In order to generate a clear profile of mucin expression patterns in health and disease different variables must be analyzed, this can alter the expression. Understanding the various molecular mechanisms in controlling mucin gene and protein expression is essential as it could lead to the invention of novel therapeutic modalities to treat disease of the upper airway.(Ali and Pearson, 2007) Mucosal tissues represent the site of infection or the route of access for many bacteria and viruses that cause human disease. Mucins are a large glycosylated protein component of mucus. Mucin glycoproteins are produced by mucus-producing cells in the submucosal glands or the epithelium. They are responsible for the viscous properties of mucus.

The glycocalyx is formed underneath the mucus layer, it’s made up of highly diverse glycoproteins and glycolipids. A major constituent of the glycocalyx are the membrane-anchored cell-surface mucin glycoproteins. Mucins have a “bottle brush” appearance as each mucin forms a filamentous protein carrying 100s of complex oligosaccharide structures. The extended conformation caused by dense glycosylation allows the molecules to occupy large volumes. The expression of specific glycosyl transferases determine the carbohydrate structures present on mucins. Therefor mucin glycosylation is controlled by genetics, tissue specific enzyme expression, and host and environmental factors influencing transferase expression. Mucins are divided into three distinct subfamilies: cell surface mucins, secreted gel-forming mucins and secreted non-gel-forming mucins. Gel forming mucins are the major constituent of mucus and are responsible for its viscoelastic properties.(Linden et al., 2008)

Mucin glycoproteins play an important role in the innate immune system by providing a first line of defense against pathogens and by acting as a physical barrier against enzymatic, chemical and mechanical insult.(Pritchard et al., 2019) They have direct antimicrobial activity or carry other antimicrobial molecules. They also have the ability to opsonize microbes to aid clearance. (Linden et al., 2008) Although mucins are important in defense, mucin barriers can hinder drug delivery. The inhaled agents bind to the mucins and are removed by mucociliary clearance. Interfering with the muco-adhesive interactions, allowing agents to cross the mucin-protective layer of the lung, would significantly improve drug delivery.(Pritchard et al., 2019)

Altered structure of mucins in CF

Mucins are important as they form the gel constituents in CF sputum. Modifications in mucins changes in the viscoelastic properties of mucus, as the addition of charged residues influences mucin aggregation. CF mucins have increased levels of galactose, fructose, N-acetylglucosamine, sulphate and sialic acid. The increases in glycosylation and branching of CF mucins have been shown to result in a higher tendency to gel and impede transport in vivo. Mucins in CF may also exhibit increased levels of sugar determinants during inflammation and infection (Pritchard et al., 2019)

Mucin glycosylation can alter in response to mucosal infection or inflammation, and this may be an important mechanism for unfavorably changing the niche occupied by mucosal pathogens (Linden et al., 2008)

The airway mucins in cystic fibrosis patients are over sulfated, this feature is a primary defect of the disease. The airway mucins in severely infected CF patients are also highly sialylated. They express sialylated and sulfated Lexis X determinants, which is a carbohydrate structure found on the non-reducing end of the mucin structure. This causes severe mucosal inflammation or infection. (Lamblin et al., 2001)

Figure 2(Burgel et al., 2007)

The figure shows the quantification of mucous glycoconjugates and mucins in the epithelium. The open symbols represent epithelium controls and the solid symbols represent patients with CF.

Pseudomonas Aeruginosa in Cystic fibrosis patients

One of the major causes of high morbidity and mortality in CF patients is pseudomonas aeruginosa. Pseudomonas aeruginosa is a gram-negative opportunistic pathogen, therefore it causes diseases when a person’s immune system is already impaired. For this reason, CF lungs are commonly infected by P. aeruginosa.

Pulmonary function starts to decline at an accelerated rate once infected with P. aeruginosa. “P. aeruginosa mucoid conversion within lungs of CF patients is a hallmark of chronic infection and predictive of poor prognosis”.(Malhotra et al., 2018)

Pseudomonas aeruginosa can be found widely in the environment. They are common pathogens involved in infections acquired in a hospital setting. When healthy people are infected with P. aeruginosa their infections are generally mild, however CF patients have weakened immune systems and will therefore suffer with more severe infections.

Once entering cystic fibrosis airways, P. aeruginosa is virtually impossible to eradicate due to its genome plasticity which allows it to adapt to the extremely stressful CF environment. Chronic infections can persist for years or decades. The challenging selective pressures caused by typical CF conditions such as low oxygen availability, interspecies competition, biofilm growth, the immune system, oxidative stress and antibiotic treatment drive P. aeruginosa. P. aeruginosa progressively generates phenotypes specifically adapted to CF airway conditions.(Sousa and Pereira, 2014) Because of this, early eradication of P. aeruginosa is very important as it avoids or at least retards the development of chronical infections and therefore preserving the lung function. However, some antibiotics fail to eradicate infection causing serious complications as the resistance subpopulations emerge. This is how chronic infections are established.(Sousa, Monteiro and Pereira, 2018)

Interaction between P. aeruginosa and CF mucins

An overabundance of mucus in CF airways provides a favourable niche for P. aeruginosa to grow. When comparing CF to non CF individuals the mucins recovered from CF airways are enriched in sialyl-Lewis x , this is a preferred binding receptor for P. aeruginosa. The levels of this sugar present directly correlate with the severity of infection in CF patients. Pulmonary infections caused by P. aeruginosa are a critical concern for CF patients, approximately 95% of patients are colonized with P. aeruginosa by the age of three. Pulmonary failure results in high morbidity and mortality in CF patients. Overproduction of hyper-viscous mucus and impeded mucociliary clearance of trapped microbes contribute to P. aeruginosa colonization in the CF airways. Mucin glycoproteins contain a diverse population of carbohydrate chains on their structure which have been shown to be receptors for bacteria. These mucin glycoproteins are a major component of airway mucus. Mucins in the airways have an intraluminal location, this is where microbes first interact in the lung. As previously mentioned CF mucins are enriched with the tetra-carbohydrate moiety sialyl-Lewis x. The enzymes that are crucial for the synthesis of this sugar, are upregulated during pulmonary inflammation. The levels of sialyl-Lewis x glycosylation on airway mucins directly correlate with the severity of the infection in CF patients. (Jeffries et al., 2016)

As well as binding to CF mucins, P. aeruginosa is also directly linked to mucus over production. P. aeruginosa lipopolysaccharide up regulates transcription of the mucin gene MUC 2 in epithelial cells. There is indication that the CFTR mutation is linked to three abnormalities which favour the onset and persistence of P. aeruginosa infection in the airways. The first abnormality is the undersialylated cell surface glycolipids that act as P. aeruginosa binding sites. The second abnormality is the decreased activity of bronchial bacteriolytic substances due to abnormal airway surfaces. The third is the impaired capacity for bronchial epithelial cells to clear P. aeruginosa by endocytosis. Overall the onset of P. aeruginosa in CF lungs causes lung deterioration. (Li et al., 1997)

There was a study carried out by (Flynn et al., 2016) to examine the possibility that mucins serve as an important carbon source for P. aeruginosa. The study concluded that P. aeruginosa was unable to efficiently utilize mucins in isolation, however they found that anaerobic, mucin-fermenting bacteria could stimulate the robust growth of P. aeruginosa, when provided intact mucins as a sole carbon source. Microorganisms typically defined as commensals may contribute to airway disease by degrading mucins, this provides nutrients for pathogens that would otherwise be unable to obtain carbon from the lung.

1. Ali, M. S. and Pearson, J. P. (2007) ‘Upper airway mucin gene expression: A review’, Laryngoscope, 117(5), pp. 932–938. doi: 10.1097/MLG.0b013e3180383651.
2. Antoniou, S. (2016) ‘Cystic fibrosis Key points’, Medicine. Elsevier Ltd, 44(5), pp. 1–5. doi: 10.1016/j.mpmed.2016.02.016.
3. Burgel, P. R. et al. (2007) ‘A morphometric study of mucins and small airway plugging in cystic fibrosis’, Thorax, 62(2), pp. 153–161. doi: 10.1136/thx.2006.062190.
4. Davies, J. C., Alton, E. W. F. W. and Bush, A. (2007) ‘Cystic fibrosis’, British Medical Journal, 335(7632), pp. 1255–1259. doi: 10.1136/bmj.39391.713229.AD.
5. Elborn, S. and Vallieres, E. (2014) ‘Cystic fibrosis gene mutations: evaluation and assessment of disease severity’, Advances in Genomics and Genetics, p. 161. doi: 10.2147/agg.s53768.
6. Flynn, J. M. et al. (2016) ‘Evidence and Role for Bacterial Mucin Degradation in Cystic Fibrosis Airway Disease’, PLoS Pathogens, 12(8), pp. 1–13. doi: 10.1371/journal.ppat.1005846.
7. Jeffries, J. L. et al. (2016) ‘Pseudomonas aeruginosa pyocyanin modulates mucin glycosylation with sialyl-Lewis x to increase binding to airway epithelial cells’, Mucosal Immunology, 9(4), pp. 1039–1050. doi: 10.1038/mi.2015.119.
8. Lamblin, G. et al. (2001) ‘Human airway mucin glycosylation: A combinatory of carbohydrate determinants which vary in cystic fibrosis’, Glycoconjugate Journal, 18(9), pp. 661–684. doi: 10.1023/A:1020867221861.
9. Li, J. D. et al. (1997) ‘Transcriptional activation of mucin by pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease’, Proceedings of the National Academy of Sciences of the United States of America, 94(3), pp. 967–972. doi: 10.1073/pnas.94.3.967.
10. Lillehoj, E. (2017) Cellular and Molecular Biology of Airway Mucins, Physiology & behavior. doi: 10.1016/j.physbeh.2017.03.040.
11. Linden, S. K. et al. (2008) ‘Mucins in the mucosal barrier to infection’, Mucosal Immunology, 1(3), pp. 183–197. doi: 10.1038/mi.2008.5.
12. Lopes-Pacheco, M. (2016) ‘CFTR modulators: Shedding light on precision medicine for cystic fibrosis’, Frontiers in Pharmacology, 7(SEP), pp. 1–20. doi: 10.3389/fphar.2016.00275.
13. Malhotra, S. et al. (2018) ‘Mixed communities of mucoid and nonmucoid Pseudomonas aeruginosa exhibit enhanced resistance to host antimicrobials’, mBio, 9(2), pp. 1–15. doi: 10.1128/mBio.00275-18.
14. Meng, X. et al. (2017) ‘The cystic fibrosis transmembrane conductance regulator (CFTR) and its stability’, Cellular and Molecular Life Sciences. Springer International Publishing, 74(1), pp. 23–38. doi: 10.1007/s00018-016-2386-8.
15. Naehrig, S., Chao, C. M. and Naehrlich, L. (2017) ‘Cystic fibrosis – Diagnosis and treatment’, Deutsches Arzteblatt International, 114(33–34), pp. 564–573. doi: 10.3238/arztebl.2017.0564.
16. Pritchard, M. F. et al. (2019) ‘Mucin structural interactions with an alginate oligomer mucolytic in cystic fibrosis sputum’, Vibrational Spectroscopy. Elsevier, 103(June), p. 102932. doi: 10.1016/j.vibspec.2019.102932.
17. Sousa, A. M., Monteiro, R. and Pereira, M. O. (2018) ‘Unveiling the early events of Pseudomonas aeruginosa adaptation in cystic fibrosis airway environment using a long-term in vitro maintenance’, International Journal of Medical Microbiology. Elsevier, 308(8), pp. 1053–1064. doi: 10.1016/j.ijmm.2018.10.003.
18. Sousa, A. M. and Pereira, M. O. (2014) ‘Pseudomonas Aeruginosa diversification during infection development in cystic fibrosis Lungs-A review’, Pathogens, 3(3), pp. 680–703. doi: 10.3390/pathogens3030680.

Cystic Fibrosis (CF) is a genetic recessive disorder.

Cause

The cause of Cystic Fibrosis is when a mutation in the CF gene encodes cystic fibrosis transmembrane regulator (CFTR), which is a protein. The movement of salt and water inside and outside of our cells are controlled by CFTR. People with CF and the mutated CFTR protein means that their chloride channels on the cells can lead to disruption. It can also lead to very salty sweat and thick, sticky mucus.

Rate of Incidence

In United States about 30,000 people have cystic fibrosis in 2018. 1 in 2,500 to 3,500 Caucasian newborns have CF and is one of the most common inherited diseases. Every year about 1,000 people with cystic fibrosis are diagnosed. In other ethnic groups it is less common, for example, 1 in 17,000 African Americans and 1 in 31,000 Asian Americans are affected by cystic fibrosis compared to 1 in 2,500 to 3,500 in Caucasian newborns.

Symptoms

The symptoms for the lungs are thick, sticky mucus build up, widened airways and bacterial infection. Some infections like sinusitis, bronchitis and pneumonia can cause long term lung damage. Another symptom is emphysema, which is a lung disease that can be caused by CF in the lungs.

The symptoms for the pancreas are blocked pancreatic ducts, which leads to the pancreas becoming inflamed. This prevents enzymes from entering your intestines and absorbing fats and proteins in the body does not work properly.

Diagnosis

One method of diagnosis is prenatal genetic tests. These tests show if your fetus has CF or not when you are pregnant. Two tests that can show if your fetus has CF or not is the amniocentesis test and the chorionic villus sampling (CVS). Amniocentesis is a needle is put through your abdominal wall into your uterus by the doctor. The doctor then takes out a little bit of fluid from the sac around the baby and then the fluid is tested to see if the CFTR genes are normal for the baby. The second test is CVS, this is a thin tube that is put into the vagina and cervix to the placenta by the doctor. A tissue sample is then taken out of the placenta using a gentle suction. The sample is then tested to see if the baby has CF or not.

Once you get your results back from a genetic or blood test, if these tests says you potentially have CF, a doctor will make sure you have it or not by doing a sweat test. A sweat test is a useful test for seeing if you have CF because it measures the amount of salt in sweat. The doctor uses a sweat-producing chemical on the skin and with a electrical current caused by an [electrode. The sweat is then collected then analysed. To know if you have CF, your results with show high salt levels if you do have CF.

Prognosis

People with CF have good health until they reach adulthood then lung disease becomes bad to where a person could be disabled. The average life span for people with CF is about 37 years and lung complications is the main reason for people with CF to die. Statistics show that 80% of patients who receive current treatment should live to adulthood where if you do not receive treatment there is a low chance of living to adulthood.

Current Treatments

The transfer of copies of the normal CFTR gene to the relevant cells is Gene therapy. This should work because it is a single gene disorder, the airways are easily accessible and at birth the lungs are normal. A problem with gene therapy is that the airways are very difficult to target. This is because the mucociilary escalator keeps foreign particles out. Another problem is the immune response for viral and non-viral gene transfer agents because for viral gene transfer agents the issue is re-administration and for non-viral gene transfer agents it is an inflammatory response.

Lung transplantation is an option when a person with CF is having breathing problems, increasing resistance to antibiotics and lung complications. Having both lungs replaced will help get rid of bronchiectasis, which is the widening of the air ways, but it does not get rid of the other issues like sinus infections and pancreas problems.

Future Treatments

An antifungal drug called amphotericin was found using human cells and animals’ models. This antifungal drug helps lung cells function easier for patients to fight chronic bacterial lung infections. This drug is more effective than the other treatments because this drug work with any mutation even when the protein is not there.

Abstract

Cystic fibrosis (CF) is a multisystem disorder that originates in the respiratory system of individuals. It is caused by a malfunction of the cystic fibrosis transmembrane receptor protein (CFTR). Improved understanding of the CFTR gene has opened doors to better understand the disease itself through research and experimental procedures. Understanding the pathophysiology of the CFTR gene itself has also raised questions about the potential benefits of gene therapy in cystic fibrosis patients. Treatment for cystic fibrosis is prioritized on the improvement of life-threatening symptoms of the disease and the elimination of the things causing these symptoms. Overall, treatments for cystic fibrosis are complex and there are several gaps in research evidence. The purpose of this review study is to explore the pathophysiology of cystic fibrosis presented in scientific literatures and provide recent information on the diagnosis and treatment therapies.

Introduction:

Cystic fibrosis (CF) is a genetic disease that affects the respiratory system, and consequentially the digestive, reproductive, immune, and endocrine systems of the individuals effected. CF is caused by an inherited mutation in the cystic fibrosis transmembrane regulator (CFTR) gene (Donnelley & Parsons, 2018). As a recessive genetic disorder, CF is inherited when two carrier parents (who have one normal gene, and one gene with the mutation) each pass the abnormal CFTR gene to their child. The most common mutation is a deletion of phenylalanine at position 508 (ΔF508), which accounts for 70% of cases. (Nicholson & Sheppard, 2014). Cystic fibrosis is a persistent, life threatening disease that causes an accumulation of mucous in the lungs, leading to chronic symptoms and most commonly pulmonary disease (Cystic Fibrosis Overview, 2019). The thick and sticky mucous produced in the lungs of individuals with CF harbors bacteria and makes it extremely difficult to breath. This life-threatening illness is terminal; with most patients living until around age forty (Donnelley & Parsons, 2018). Though there is no cure for this disease, research advances within the last decade have provided further understanding of the disease and the improved development of therapeutic approaches in order to manage cystic fibrosis and its associated symptoms.

Cystic fibrosis effects at least 30,000 people in the United States and between 900 and 1,000 new cases are diagnosed every year. One in 29 people of Caucasian ancestry is an unaffected carrier (heterozygous) of the CF gene mutation. In the United States, cystic fibrosis occurs at a rate of 1 in 3,400 births, with most cases associated with Caucasian racial background. Most individuals with cystic fibrosis were diagnoses by five months of age; however, the average age of diagnosis was five years. Many are not even diagnosed until adulthood (Cystic Fibrosis, 2014).

Etiology

A mutation, or alteration, in the host genome affects the production of certain proteins needed for important biological functions. Almost 2,000 mutations in the CFTR gene have been found to cause cystic fibrosis (Hodges & Conlon, 2019). When there is a mutation in the CFTR gene of individuals, the production of the CFTR protein may be affected. Individuals that have cystic fibrosis disease possess these mutations in the CFTR gene. These mutations either result in the complete absence of, or reduction of the CFTR protein, or an incorrect protein with the wrong configuration (Gene Therapy for Cystic Fibrosis, 2019). The ultimate role of the CFTR gene is to maintain the flow of salt (sodium and chloride) and water across the cells that line the respiratory, digestive, and reproductive tracts. A mutation in this gene therefore decreases the flow of salts through the epithelia of multiple organs, including the lungs, sweat glands, vas deferens, liver, and intestines. (Pranke et al., 2019) The decreased flow of salt ions results in a reduction of water in the fluid lining the airways. The lack of water production in these airways drives the accumulation of abnormally thick and sticky mucous that underlies chronic lung inflammation and recurrent bacterial infections, leading to continuous lung deterioration. (Pranke et al., 2019). The inactive flow of water and salt ions allows for increased inflammation and thus inflammatory response. The neutrophils secreted by the body’s immune system further enhances inflammation because they produce elastase and proinflammatory cytokines (Nichols and Chmiel, 2015). This vicious cycle of airway obstruction, inflammation, and persistent infection leads to decrease in lung function, eventually leading to respiratory failure and death. Clogged mucus secretions can lead to additional problems in other organ systems in the body as well (Cystic Fibrosis, 2014).

Pathophysiology (symptoms)

There are various symptoms associated with cystic fibrosis disease. Among the most common and consequentially the most life-threatening of symptoms are those associated with the respiratory system, ultimately leading to the individual’s inability to breath. This is a result of damaged airways, or bronchiectasis, which makes it difficult for the transfer of air in and out of the lungs and clear the mucous from the airways. The thickened mucous provides an ideal breeding ground for bacteria and fungi which could cause additional infections such as: bronchitis, sinus infections, or pneumonia. Patients with more progressive forms of cystic fibrosis have hemoptysis, or coughing up blood. This happens due to the thinning of the airway walls over time. Other respiratory associated symptoms include pneumothorax which involves chest pain and breathlessness, and respiratory failure, which happens as a result of severe damage to the lung tissues that hinders the function of the lungs (Cystic Fibrosis, 2019).

Cystic fibrosis also causes digestive system complications such as: nutritional deficiencies, diabetes, blocked bile duct, intestinal obstructions, and distal intestinal obstruction syndrome (DIOS). Nutritional deficiencies happen as a result of thickened mucous preventing the transfer of digestive enzymes from pancreas to the intestines; this inhibits the body’s ability to absorb protein, fats, and some vitamins. Many CF patients also develop diabetes because the pancreas is unable to produce insulin—the hormone necessary to use sugar. Blocked bile ducts prevent the transfer of bile from the liver to the gallbladder, leading to liver problems and sometimes gallstones. That malfunctions of particular components of the digestive system could lead to even more complication in and, in later stages of cystic fibrosis, organ failure. (Cystic Fibrosis, 2019).

Treatments

Most CF patients die from infection present within the lower respiratory tract due to the accumulation of harmful bacteria within the viscous mucous in the lungs. The thickened mucosal lining of the airways harbors pathogens such as Staphylococcus aureaus, Haemophilus influenzae, and Pseudomonas aeruginosa. (Sheppard & Nicholson, 2014) The resulting immune response generated by the body to fight the infections imposed by these pathogens ultimately leads to pulmonary disease due to the lung damage caused by the increased inflammatory response.

Antimicrobial Treatments:

Several studies have been conducted to eradicate the detrimental side effects of bacterial infections on CF patients in an attempt to treat the symptoms of the disease and increase lifespan by slowing or eliminating pulmonary disease. One of the main causes of reoccurring pulmonary infections and the resulting life-threatening lung conditions in CF patients is caused by the bacteria Staphylococcus aureus; within the first three years of life. (Ranzenbacher et al., 2019). Two strains of this bacterium block the respiratory pathways of infected individuals: methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA). The most detrimental of these strains is MRSA considering the difficulty in treating the resulting infection with antibiotics. (Ranzenbacher et al., 2019).

In an attempt to eradicate MRSA and MSSA in CF patients, studies were conducted analyzing the effect of S. aureus colonization in the airways of CF patients and the different procedures for antimicrobial treatment. One specific study focused on the long-term antibiotics, rifampicin and fucidin in the attempt to eradicate the MRSA and MSSA. Eradication proved successful in patients exhibiting intermittent (less than 50 percent) bacterial colonization. With this, the data showed that the process of eradication of S. aureus in particular can improve patients most in early stages of CF when the percent of S. aureus colonization is lower than that of patients possessing a more progressed form of CF. (Esposito et al., 2019).

Apart from Staphylococcus aureus infection, Pseudomonas aeruginosa is another life-threatening bacterium that resides in the respiratory systems of cystic fibrosis patients. P. aeruginosa is noted as the major cause of mortality in CF patients. The gram-negative bacterium possesses virulence factors that secrete toxins for overcoming immune response produces by the host. (Bhagirath et al., 2016).

In patients with CF, their immune systems are compromised, making it an especially favorable environment for pathogens like P. aeruginosa. With this, there have been few experimental attempts to eradicated P. aeruginosa in CF patients. A 2014 study cultured the respiratory microbiomes of 279 CF patients, several patients exhibited the eradication or the slowed growth of P. aeruginosa after administration of several antibiotics and additional treatment methods (Kenny et al., 2014). These procedures are termed antibiotic eradication therapy (AET). The use of aggressive AET proved successful in the majority of adults exhibiting first-time P. aeruginosa infection (Kenny et al., 2014). Ultimately, this is important because the number of patients with CF entering adult care with no history of P. aeruginosa infection is increasing; therefore, these patients have an increased need for AET in order to help prevent chronic infections produced by P. aeruginosa and the resulting progression of lung damage and the disease in general.

Gene Therapy:

Scientists are exploring several strategies concerning gene therapy in patients with cystic fibrosis. With advancing technologies, the mechanism of gene therapy has become more achievable with new methods for genome editing such as Zinc-finger, CRISPER, and TALENs (Vargas et al., 2016). Gene therapy is the process by which the correct gene is incorporated into the host genome in an attempt to allow the host to construct more normal copies of the wild-type gene. In this case, the mutated form of CFTR gene would coexist with the normal CFTR gene, and the presence of the normal gene relocates to the epithelial cell layer in the airways with the goal of replacing the mutated gene and expressing the functional CFTR protein (Gene Therapy for Cystic Fibrosis, 2019). Although gene therapy has potential to make a significant impact in the lives of individuals with CF and possibly cure the disease as a whole, there are several limitations associated with gene therapy. First, determining the correct and most relevant plasmid DNA molecule model is important. Second, natural barriers such as mucus, immune responses, and intracellular limitations inhibit gene transfer into the lungs. Finally, gene therapy would need to be administered several times throughout the lifetime of the individual due to the fact that the epithelium lining the airways is constantly regenerating. (Pranke et al., 2019). Another disadvantage of gene therapy in CF patients is that this strategy only works in the specific cells that receive the therapy. This being said, gene therapy could be used to treat the lungs, but it will not help the cells in other organ systems throughout the body that are affected by CF, such as the digestive system (Gene Therapy for Cystic Fibrosis, 2019). Taking these disadvantages into consideration, the selection of the appropriate method of gene therapy is essential for success of the treatment. There are three types of gene therapies that have potential to treat cystic fibrosis: integrating gene therapy, non-integrating gene therapy, and RNA therapy (Gene Therapy for Cystic Fibrosis, 2019).

Integrating gene therapy involves the incorporation of DNA containing the corrected CTFR gene into the host genome. This is a permanent integration which could be beneficial in that the patient may only need to receive the therapy a small number of times; however, there is little control in where exactly the gene will be inserted into the host genome associated with this therapy type (Gene Therapy for Cystic Fibrosis, 2019). There are several forms of integrating gene therapy that have been used in the treatment of patients with certain cancers, however, research is still underway in order to determine a beneficial effect of this type of gene therapies in CF patients. Recent studies have examined lentiviral vectors and non-viral vectors as integrating vectors into CF patient genomes (Cooney et al., 2018).

Non-integrating gene therapy involves the incorporation of the correct copy of the CTFR gene into the host genome, without disrupting the genome itself. The gene of interest is simply placed within the genetic information of the individual, but still remains separate from the individual. This form of gene therapy can be beneficial concerning the limited side effects that occur. Though, a disadvantage to this type of therapy is that is not permanent because the new CTFR is not in direct correlation with the rest of the host genome. For this reason, non-integrating gene therapy needs to be administered several times during treatment in order to be beneficial.

In recent years, use of several different types of viral vectors are of high interest in the research of gene therapy for cystic fibrosis patients. A study published in March of 2019 examined the use of lentiviral vectors in the potential prevention of cystic fibrosis lung disease. The lentiviral vector is a type of retrovirus that can transduce in dividing and non-dividing cells. Successful therapies using this type of vector would be beneficial in CF patients especially because they can provide long-term transgene expression. In the particular study in 2019, the lentivirus was evaluated based on successful platforms that vector produced in earlier studies with HIV, FIV, EIAV, and SIV (Marquez Loza et al., 2019). Furthermore, a study in 2016 worked to identify a variety of pre-clinical trial components associated with the lentiviral vectors: mapped integration sites, characterized transduced cell types, assessed acute toxicity, determined the effects of pre-existing immunity on transduction efficiency and toxicity, assessed CFTR function of our lead vector, and quantified vector stability in delivery devices suitable for a first-in-man trial. After careful evaluation of all these necessary components for gene therapy, the study supported the proposed use of the particular lentiviral vector in a future first-in-man clinical trial (Alton et al., 2016).

Cystic Fibrosis is a detrimental disease that comes with numerous complications associated with several different organ systems within the human body. The etiology, pathophysiology, and treatments provide a solid foundation to the understanding of Cystic Fibrosis. As a genetic disease, there is no cure; however, research is directed toward therapies that target the symptoms of the disorder in order to make the disease more manageable for individuals with CF. With the development of new genetic and biomedical technologies, future direction aims to use gene therapy as a means for treating the disease. There is still a lot that is unknown about gene therapy, and though there is no cure for cystic fibrosis, there is hope that developing research will eventually provide answers to fix the mutated CFTR gene permanently. The ultimate goal is to change CF from cystic fibrosis to cure found.

References

1. Alton, E. W., Beekman, J. M., Boyd, A. C., Brand, J., Carlon, M. S., Connolly, M. M., … Zhu, J. (2017). Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax, 72(2), 137–147. doi:10.1136/thoraxjnl-2016-208406
2. Bhagirath, A. Y., Li, Y., Somayajula, D., Dadashi, M., Badr, S., & Duan, K. (2016). Cystic fibrosis lung environment and Pseudomonas aeruginosa infection. BMC pulmonary medicine, 16(1), 174. doi:10.1186/s12890-016-0339-5
3. Cooney, A. L., P.l B. McCray, Jr and Patrick L. Sinn (August 24th 2015). Integrating Viral and Nonviral Vectors for Cystic Fibrosis Gene Therapy in the Airways, Cystic Fibrosis in the Light of New Research, Dennis Wat, IntechOpen, DOI: 10.5772/60977
4. Cooney, A. L., McCray, P. B., Jr, & Sinn, P. L. (2018). Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward. Genes, 9(11), 538. doi:10.3390/genes9110538
5. Cystic Fibrosis. (2014) American Thoracic Society. Retrieved from https://www.th oracic.org/pat ients /lung-disease-week/2014/cystic-fibrosis-week/general-info.php
6. Cystic Fibrosis. (2019). Mayo Clinic. Retrieved from https://www.mayoclinic.org/diseases- conditions /cystic-fibrosis/symptoms-causes/syc-20353700
7. Cystic Fibrosis Overview. (2019). Stanford Children’s Health. Retrieved from
8. https://www.stanfordchildrens.org/en/topic/default?id=cystic-fibrosis-overview-90- P09526
9. Donnelley, M. and D. W. Parsons (2018) Gene Therapy for Cystic Fibrosis Lung Disease: Overcoming the Barriers to Translation to the Clinic. Frontiers in Pharmacology. 9:1381. doi: 10.3389/fphar.2018.01381
10. Esposito S, Pennoni G, Mencarini V, Palladino N, Peccini L and Principi N (2019) Antimicrobial Treatment of Staphylococcus aureus in Patients With Cystic Fibrosis. Frontiers in Pharmacology. 10:849. doi: 10.3389/fphar.2019.00849
11. Gene Therapy for Cystic Fibrosis. (2019). Cystic Fibrosis Foundation. Retrieved from https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Gene- Therapy-for-Cystic-Fibrosis/
12. Hodges, C. A., & Conlon, R. A. (2018). Delivering on the promise of gene editing for cystic fibrosis. Genes & diseases, 6(2), 97–108. doi: 10.1016/j.gendis.2018.11.005
13. Kenny SL, Shaw TD, Downey DG, et al. Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis. BMJ Open Respiratory Research 2014;1:e000021. doi: 10.1136/bmjresp- 2014-000021
14. Marquez Loza, L. I., Yuen, E. C., & McCray, P. B., Jr (2019). Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease. Genes, 10(3), 218. doi:10.3390/genes10030218
15. Nichols, D. P., J. F. Chmiel. (2015). Inflammation and Its Genesis in Cystic Fibrosis. Pediatric Pulmonology. 50:S39-S56. Doi: 10.1002/ppul.23242
16. Pranke I, Golec A, Hinzpeter A, Edelman A and Sermet-Gaudelus I (2019) Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine. Frontiers in Pharmacology. 10:121. doi: 10.3389/fphar.2019.00121
17. Ranzenbacher, L., Y. Song, A. Merchant, and P. G. Middleton. (2019). Intermittent Colonization with Methicillin-Resistnant Staphylococcus aureus Can Be Eradicated from the Airways of Adults with Cystic Fibrosis. Antibiotics 8, no. 3: 113
18. Vargas, J.E., Chicaybam, L., Stein, R.T. et al. Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives. J Transl Med 14, 288 (2016) doi:10.1186/s12967-016-1047-x

Abstract

The genetic disorder that I choose was Cystic Fibrosis, also known as CF. CF is caused by a change and/or mutation in the cystic fibrosis transmembrane conductance regulator also known as CFTR gene. People who have CF inherit two copies of the CF gene, one gene from each parent. The CFTR gene controls the flow of salt and fluids in and out of your cells. Since the CFTR gene controls if it does not as it was meant to, then sticky mucus builds up in the body. Cystic Fibrosis affects mainly the lungs and the digestive system. People who have CF are prone to contracting lung infections. There is no cure for Cystic Fibrosis at the current time.

History

The earliest record of Cystic Fibrosis is in 1983 from an American pathologist Dr. Dorothy Andersen who provided the first description of the disorder in the medical literature. Dr. Dorothy Andersen called the disease “cystic fibrosis of the pancreas” based on the children who died of malnutrition. In 1948, Dr. Paul di Sant’ Agnese found that the sweat of children who had CF abnormally high salt concentration. In 1955, The Cystic Fibrosis Foundation was formed by a group of concerned parents who were determined to save the lives of their children. The predicted age of survival changed from 10 in 1962, 16 in 1970, and in 1980 the age was 18. In 1963, the US CF Foundation wrote a guide for diagnosing cystic fibrosis. The medical centers devoted to CF went from two to more than 100 through 1961-1978. In 1989, a team of scientists discovered the defective cystic fibrosis transmembrane conductance regulator (CFTR) and open the door to understanding the disease at the most basic level, and the predicted age of survival changed to 19. In 1993 and 1997, the FDA approved of Pulmozyme and TOBI two different antibiotics designed for CF. These helped reduce hospital stays and improve lung function. In 2000, the median age improved to 32 and in 2004, studies and the University of North Carolina found that hypertonic saline helps clear CF mucus. One of the first oral drugs to work on a cellar level (VX-770) was found in 2006. The first march was held in 2007 to educate elected officials about the need for continued funding for NIH, the FDA, and other drug development and research programs. In 2008 phase two studies of the oral compound VX-770 showed an increase in lung function and improvements in overall health and well-being, proving that it is possible to treat the root cause of CF. The foundation raised $175 million through the milestones campaign in 2010. The money that was raised was used to fund research projects, buy better equipment, etc. Throughout 2011- 2013, phase 3 clinical trials of ivacaftor (VX-770) show profound results and the foundation a new drug application was submitted under the trade name Kalydeco, the FDA approved of ivacaftor/Kalydeco for a small group of people 6 and older, and two large international phase 3 trails of ivacaftor. In 2016, the FDA approved the ivacaftor for children with CF ages 6 to 11 who have two copies of F508del mutation (one of the many types of CF mutations). This made nearly 11,000 in the US eligible for the treatment. In 2018 the foundation maintains a robust pipeline of potential therapies that target the disease at every angle.

Symptoms

The most common symptoms of Cystic Fibrosis are very salty-tasting skin, persistent coughing at times without phlegm, wheezing, coughing blood, frequent lung infections such as pneumonia or bronchitis, greasy, bulky stools or difficulty with bowel movements, infertility especially in males, and poor weight gain in spite of excessive appetite. More extreme symptoms are pancreatitis, or inflammation of the pancreas, diabetes, nasal polyps or small fleshy growths found in the nose, jaundice/ yellow skin, and Pneumothorax which collects air in the space that separates the lungs from the chest wall. This condition can cause chest pain and breathlessness. If you experience most of the common symptoms and at least two of the more extreme symptoms, please see your local doctor to see if you or your child have Cystic Fibrosis.

Causes

Some causes of cystic fibrosis are family history and race. Since Cystic Fibrosis is a genetic disorder you are born with CF. People with CF get CF from their parents. To get it you must have two copies of the defective CF gene. One copy from each parent, so both parents must have at least one copy of the defective gene. One of the causes of Cystic Fibrosis is family history because it is an inherited disorder, so it runs in families. Race is another type pf cause even though it occurs in all races, it is most common in white people of Northern European ancestry. Cystic Fibrosis is one of the most common genetic disorders and 1 in 2,5000-3,500 Caucasian-Americans, 1 in 4,000-10,000 Hispanic-Americans, 1 in 15,000-20,000 African Americans, and 1 in 100,000 Asian-Americans. Also, CF cannot transmitted.

Treatments

There are currently many treatments to help slow down the process CF. One treatment is antibiotics to treat and prevent lung infections, or anti-inflammatory medications to help with swelling in the airways of your lungs. They include ibuprofen and corticosteroids.