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Biology Depth Study - Cystic Fibrosis

Introduction:
Cystic Fibrosis is a genetically-inherited disease that primarily causes severe damage to
the lungs and digestive system as it causes a defectivity in the secretion of saliva, sweat
and mucus in the exocrine system. These secreted fluids are normally thin and smooth,
however, in individuals with cystic fibrosis, the defective gene causes adhesive
secretions to be produced, blocking tubes and passageways within the body, especially
in the lungs, pancreas and liver. This causes bacteria to build up, due to the thick
mucus layer, within the lungs resulting in persistent infections, leading to drastic lung
damage and, in severe cases, the death of the patient. Cystic Fibrosis is an autosomal
recessive gene, meaning that it must be inherited from both parents however, it can skip
over some generations.

Currently, there is no guaranteed cure for cystic fibrosis so patients must manage and
treat their condition daily, for the rest of their lives. The most common treatments are
supplement capsules to help digest food and daily intensive physiotherapy to clear the
lungs. However, a new method of genetic engineering known as ‘Gene Therapy’ was
developed where its process involves a new, functioning cystic fibrosis transmembrane
conductance regulator (CFTR) gene being inserted into the cells of the body, allowing
the cells to make normal CFTR proteins.

However, although Gene Therapy has its benefits where it has the potentiality to cure
cystic fibrosis, improve the condition of an individual's lungs and digestive system, but it
does come with its risks in that it’s a very expensive procedure, costing $750,000 USD
for the first treatment and $375,000 USD for additional years (as it requires on-going
treatment to be effective), but it also has an unreliable delivery method where the
enzyme may be eliminated by the immune system before it starts to work, which might
cause the body to attack itself, causing further damage to the patient.

With its potentiality of curing cystic fibrosis contrasted with its extremely high cost and
unreliability, the question remains: ‘Is gene therapy worth the risks and expenses to
cure a patient with cystic fibrosis?’ ’

About Cystic Fibrosis:

Cystic Fibrosis is a progressive genetic disease that causes persistent lung infections
and limits the ability to breathe over time. Individuals with cystic fibrosis have mutations
in their CFTR gene which causes the CFTR protein to become dysfunctional. It is
caused by mutations to a gene on chromosome 7, one of the 23 pairs which are
inherited from the parents [Duvys Media, 2019]. The most common mutation, ΔF508, is a
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deletion of three nucleotides that results in a loss of the amino acid phenylalanine at the
508th position on the protein [Guimbellot, Jennifer; Sharma, Jyoti; Rowe, Steven M, 2017]. When this
occurs, the protein is unable to move chloride to the cell surface, which causes less
water to be attracted, thus the mucus becomes thick and sticky clogging the airways in
the lungs and trapping bacteria, leading to infections, inflammation and respiratory
failure. In the pancreas, digestive enzymes are unable to be released due to the buildup
of thick mucus, disallowing the body to absorb nutrients from food, resulting in
malnutrition and poor growth. In the liver, the bile duct - a series of tubes leading to the
small intestine - can be blocked by the thick mucus, causing liver disease. In men,
cystic fibrosis can affect their ability to have children as the thick mucus may block the
sperm canal, making it impossible to produce semen.

The ΔF508 deletion accounts for 66%–70% [Kumar, Fausto, Abbas, Mitchell, 2008] of CF cases
worldwide and 90% of cases in the United States; however, over 1500 other mutations
can produce CF [Bobadilla, Macek, Fine, Farrell, 2002]. A study was performed by the National
Institutes of Health (USA) in 2012 and found that CF occurs in 1 in 2,500-3,500 white
newborns while in other ethnic groups it affects about 1 in 17,000 African Americans
and 1 in 31,000 Asian Americans, outlining how prevalent the disease is in just the US
alone [National Library of Medicine (NIH.),2012].

Although most people have two working alleles of the CFTR gene, only one is needed
to prevent cystic fibrosis. CF develops when neither allele, passed on by the parents
can produce a functional CFTR protein and thus, CF is considered an autosomal
recessive disease.

Individuals who suffer from cystic fibrosis experience a variety of symptoms with the
most common being chronic coughing with phlegm, salty-tasting skin and lung
infections, which the most common include, pneumonia, bronchitis or bronchiolitis.
Gastrointestinal complications also occur such as diarrhoea, heartburn and severe
constipation as well as respiratory symptoms including pulmonary hypertension
(increased blood pressure within arteries), wheezing and shortness in breath which
causes overall body fatigue and the inability to exercise. Cystic fibrosis also causes
developmental issues such as delayed puberty and slow growth despite individuals
having a good diet.

Current approaches towards the diagnosis of cystic fibrosis include infant sweat and
genetic testing. Sweat testing the concentration of chloride excreted from sweat and
whether the infant has defective chloride channels that are caused by CF while genetic
testing involves the identification of changes in DNA that may result in CF occurring. As
for prevention, cystic fibrosis cannot be prevented however a newly developed method
of treatment known as ‘Gene Therapy’ may be a possible solution as it inserts the
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correct CFTR gene into the body in the hopes that the body will create more correct
CFTR genes. However, this method can force the body to harm itself as the insertion of
an unknown CFTR gene may result in the immune system attacking itself, causing
additional consequences to the individual.

About Gene Therapy:

Gene therapy is an experimental technique which focuses on the utilisation of the
curative delivery of new DNA into a patient's cells as a way to treat, and possibly cure, a
genetic disease. The new DNA usually contains a healthy, functioning gene to correct
the effects of the same dysfunctional gene that is within an individual’s cells. In the case
of cystic fibrosis, the process of gene therapy involves the insertion of a correctly
functioning cystic fibrosis transmembrane conductance regulator gene within a new
DNA sequence into the epithelial cells in the lung airways where its presence would
then allow the cells to produce normal CFTR proteins [Burney, Davies,2012]. The CFTR
gene is transported into the lungs through a delivery mechanism known as a plasmid
vector, derived from other synthetic molecules, which will allow the new gene to safely
pass through the thick mucus layer, caused by cystic fibrosis, situated above the lungs
[Alton et al., 2015].

This form of treatment falls under the category of Recombinant DNA Technology where
a new, functioning CFTR gene is developed through molecular cloning in order to create
a new DNA sequence which cannot be found within an individual’s genome who is
suffering from cystic fibrosis. The use of a plasmid vector to transport the new CFTR
gene is another factor which identifies gene therapy as part of recombinant DNA
technology as in other scientific methods, the use of a plasmid vector to transport
foreign DNA fragments into an individual’s cells is used as a safe form of transport into
the somatic and germ-line cells of the body [Rosano, Germán, Ceccarelli, Eduardo,2014].

Evaluation of Risks and Benefits:

With this new upcoming method of Gene Therapy to treat cystic fibrosis come to its
benefits and risks which impact the individual being treated. In a post in 2018, the
company Biolyse, a pharma corporation specialising in bioinformatics and biotechnology
including Gene Therapy, stated that two benefits of gene therapy are that its effects are
long-lasting and can eradicate cystic fibrosis and improve the overall quality of life of the
individual [Biolyse, 2018].

By inserting a functional CFTR gene to combat the defective gene there are limited
chances of respite which will result in a symptom-free for life for the individual.
Furthermore, Biolyse states that gene therapy is not just a remedy to the individual
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suffering from a given condition, but it covers the entire generation as the removal of a
dysfunctional CFTR gene won’t transfer the defective genes to their offspring, but the
new functional gene [Biolyse, 2018]. This is extremely hopeful as this effectively outlines
the potentiality of a successful cure for cystic fibrosis that ultimately lasts for generations
as the treated individual would successfully pass on their functional CFTR gene to their
offspring, eliminating the cystic fibrosis allele from entering meiosis.

Biolyse also outlines how the successful result of gene therapy will improve the quality
of life of the treated individual as they won’t have to live with the symptoms of cystic
fibrosis [Biolyse, 2018]. This is also aimed at male infertility caused by cystic fibrosis as its
treatment would allow previous infertile males to have the ability to have children of their
own with the added benefit that they will pass on their healthy CFTR gene. This is
another extremely hopeful outcome as cystic fibrosis has been the cause of shorter life
expectancies and, in the past, was known to be incurable thus, seemingly ruining the
lives of tens of thousands of people around the world. With the evident breakthrough of
gene therapy, those thousands of individuals will be able to successfully live longer
lives, have families of their own and overall enjoy their lives.

However, Biolyse has also identified two risks that come with the use of gene therapy to
treat cystic fibrosis. They found that gene therapy has no guarantee that it will
effectively cure genetic disease and may lead to additional immunity risks [Biolyse, 2018].
Biolyse also outlines how gene therapy is a costly procedure and will be troubling for
individuals to afford such treatment.

Due to gene therapy still in its experimental stage, there is a possibility that treatment
may worsen the effects of cystic fibrosis due to incompatibility issues and spontaneous
immune responses. Since the procedure requires a foreign DNA sequence to enter the
body, the immune system may attack either the plasmid vector carrying the sequence or
the body itself which will cause the procedure to fail and cause additional damage to the
individual. Because of this, gene therapy is still unreliable and may require multiple
procedures or a full revision of the method before it is successful. This is an unfortunate
consequence as gene therapy currently serves as the closest cure to cystic fibrosis so
for individuals suffering from the disease, it is their only option which may
unsuccessfully backfire upon initial treatment and worsen their condition.

Biolyse has also indicated the extremely high cost of undergoing gene therapy likely
due to its leading-edge, sophisticated equipment and the level of expertise required in
order to perform the procedure [Biolyse, 2018]. The cost of gene therapy in the first year is
around $750,000 USD while other occurring years will be an additional $375,000 to
$875,000 USD, making it extremely unaffordable to most of the population [March,2019].
This, unfortunately, will potentially create socioeconomic segregation between the
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affluent and the poor as only the people that can afford the treatment will be disease-
free while the rest of the population, unable to afford such a high expense, will have the
burden of suffering from cystic fibrosis. This extremely high price point is also an
unfortunate detriment to many individuals as due to the unreliability of the procedure, it
would likely require recurring procedures before it is finally successful which, when
accounted for its price, is an extremely overwhelming cost for most of society.

Conclusion:
In summary, cystic fibrosis is a deadly autosomal recessive disease that causes chronic
lung infections and limits the ability of the individual to breathe and absorb key nutrients
over time due to the common build-up of mucus in the lungs and pancreas. However,
the procedure of gene therapy holds promise for the future treatment of cystic fibrosis
due to its potentiality of curing the genetic disease and its chance to increase the overall
quality of life of the individual. However, it does come with its risks in which it holds an
extremely high price tag and is currently extremely unreliable due to it only being in its
experimental stage but poses as the current only option of treatment for patients with
cystic fibrosis. So, in answer to the question:‘Is gene therapy worth the risks and
expenses in order to cure a patient with cystic fibrosis?’,currently, is no since its
extremely high cost and limited chances of success resulting in the potential worsening
of the current condition of the individual is just not worth the slight chance that it may
cure the genetic disease. Although current treatments such as taking a multitude of
supplements to suppress the symptoms as well as dealing with the disease may be
exhausting and painful, waiting for the success rate of gene therapy to increase due to
improvement in technology in the future is recommended as the individual won’t have to
deal with the high expenses and worsened symptoms and can instead enjoy the relief of
being disease-free when gene therapy becomes more successful.

References List:

March, R.J. (2019). Why This New Gene Therapy Drug Costs $2.1 Million | Raymond J. March. [online] Fee.org.
Available at: https://fee.org/articles/why-this-new-gene-therapy-drug-costs-21-million/.
Biolyse (2018). Gene Therapy Pros and Cons. [online] Biolyse. Available at: http://www.biolyse.ca/gene-therapy-
pros-and-cons/.

Rosano, G.L. and Ceccarelli, E.A. (2014). Recombinant protein expression in Escherichia coli: advances and
challenges. Frontiers in Microbiology, 5.
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Cff.org. (2019). Gene Therapy for Cystic Fibrosis. [online] Available at: https://www.cff.org/Research/Research-
Into-the-Disease/Restore-CFTR-Function/Gene-Therapy-for-Cystic-Fibrosis/

Alton, E.W.F.W., Armstrong, D.K., Ashby, D., Bayfield, K.J., Bilton, D., Bloomfield, E.V., Boyd, A.C., Brand, J.,
Buchan, R., Calcedo, R., Carvelli, P., Chan, M., Cheng, S.H., Collie, D.D.S., Cunningham, S., Davidson, H.E.,
Davies, G., Davies, J.C., Davies, L.A., Dewar, M.H., Doherty, A., Donovan, J., Dwyer, N.S., Elgmati, H.I.,
Featherstone, R.F., Gavino, J., Gea-Sorli, S., Geddes, D.M., Gibson, J.S.R., Gill, D.R., Greening, A.P., Griesenbach,
U., Hansell, D.M., Harman, K., Higgins, T.E., Hodges, S.L., Hyde, S.C., Hyndman, L., Innes, J.A., Jacob, J., Jones,
N., Keogh, B.F., Limberis, M.P., Lloyd-Evans, P., Maclean, A.W., Manvell, M.C., McCormick, D., McGovern, M.,
McLachlan, G., Meng, C., Montero, M.A., Milligan, H., Moyce, L.J., Murray, G.D., Nicholson, A.G., Osadolor, T.,
Parra-Leiton, J., Porteous, D.J., Pringle, I.A., Punch, E.K., Pytel, K.M., Quittner, A.L., Rivellini, G., Saunders, C.J.,
Scheule, R.K., Sheard, S., Simmonds, N.J., Smith, K., Smith, S.N., Soussi, N., Soussi, S., Spearing, E.J., Stevenson,
B.J., Sumner-Jones, S.G., Turkkila, M., Ureta, R.P., Waller, M.D., Wasowicz, M.Y., Wilson, J.M. and
Wolstenholme-Hogg, P. (2015). Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic
fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet Respiratory Medicine, [online]
3(9), pp.684–691. Available at: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(15)00245-

3/fulltext#seccestitle10.

Davies, J., Burney and Alton, E. (2012). Gene therapy for the treatment of cystic fibrosis. The Application of
Clinical Genetics, p.29.

Genetics Home Reference (2011). Cystic fibrosis. [online] Genetics Home Reference. Available at:
https://ghr.nlm.nih.gov/condition/cystic-fibrosis.

Bobadilla, J., Macek, M., Fine, J. and Farrell, P. (2002). Cystic fibrosis: A worldwide analysis of CFTR mutations -
Correlation with incidence data and application to screening. [online] ResearchGate. Available at: Cystic fibrosis:
A worldwide analysis of CFTR mutations - Correlation with incidence data and application to screening.

Kumar, V., Abbas, A.K., Aster, J.C. and Perkins, J.A. (2018). Robbins basic pathology. Philadelphia, Pennsylvania
Elsevier.

Guimbellot, J., Sharma, J. and Rowe, S.M. (2017). Toward inclusive therapy with CFTR modulators: Progress and
challenges. Pediatric Pulmonology, 52(S48), pp.S4–S14.

www.mayoclinic.org. (n.d.). Gene therapy - Mayo Clinic. [online] Available at: https://www.mayoclinic.org/tests-
procedures/gene-therapy/about/pac-20384619?page=0&citems=10

‌Childlifesociety.org. (2019). What Causes Cystic Fibrosis: Child Life Society. [online] Available at:
https://www.childlifesociety.org/what_causes_cf.php.
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