Session A1
Paper 234
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ADENO-ASSOCIATED VIRAL VECTORS AS GENE THERAPY TO TREAT
PARKINSON’S DISEASE WITH A CASE STUDY OF VOYAGER
THERAPEUTICS
Michael Kassabian, [email protected] , Mena 3:00, Abigail Daniels, [email protected], Mahboobin 10:00
a feedback loop and continues the operation.
Neurotransmitters from the substantia nigra within the
striatum send the processed decision to the putamen for
further processing, which provides the striatum with enough
information to continue on in the process. If any part of this
operation is interrupted, movement will no longer be able to
occur [1,2].
Abstract- In humans, genes code for proteins that the body
uses to function properly. When mutated DNA is present, genes
are coded incorrectly and therefore incorrect protein synthesis
occurs. The development of malfunctioning proteins often
leads to bigger and sometimes fatal issues such as Parkinson’s
disease (PD). One field of medicine called gene therapy
involves modifying missing or mutated genes and could
potentially offer a remedy for those suffering from PD. An
emerging type of gene therapy that has been proven to be fairly
effective uses viral vectors to transport new, healthy genes to
replace damaged or missing portions of DNA. The viruses
function by exploiting the mechanisms that help the virus
reproduce.
A patient with PD has lost neurons that produce the
neurotransmitter dopamine, which is hormone that sends
information from the substantia nigra to the chemical
receptors located in the putamen. The pars compacta region
of the substantia nigra holds the dopaminergic neurons and
transmits an enzyme to the putamen. PD causes the death of
these dopaminergic neurons- as shown in Figure 1- , so the
patient progressively gets worse over time. As less dopamine
is transmitted, the presence of the enzyme that converts amino
acids into the hormone also decreases. Without the
appropriate amount of dopamine production in the basal
ganglia, consistent motor functions cannot be made and
movements cannot be controlled [3].
Viral vector gene therapy will be analyzed by
discussing the specific functions and applications of adenoassociated viruses (AAV). The virus to cell genetic transfer
will be explained through the biology of AAV and we will
show how the viruses can be used specifically to treat
Parkinson’s disease. Additionally, this paper will examine the
precise genes that are involved in PD, the systematic process
through which the symptoms can be treated by adenoassociated viral vectors, and the significant impact that this
procedure could have on the future of gene therapy.
Key Words- Adeno-associated viruses, Gene therapy,
Mutated DNA, Parkinson’s disease, Viral vectors.
DAMAGES INCURRED BY PARKINSON’S
DISEASE
The Physiological Effect
Parkinson’s disease is a degenerative, neurological
disorder that prevents movement from occurring correctly.
Considering there are almost one million Americans who face
this challenge, most people are affected in some way by this
incurable disease. The action of moving is a complex process
that involves a lot of activity in the brain before the initiation
of an action. The input of an action starts in the posterior
parietal cortex of the brain, where information is provided in
order to make a decision on the movement to be made. Action
selection then occurs in the basal ganglia, which is the region
that controls movement. The striatum, located within the
basal ganglia in the midbrain, then receives information from
University of Pittsburgh, Swanson School of Engineering
03.31.2017
FIGURE 1 [4]
Visual representation of the neurological impact of
Parkinson’s disease
Patient Symptoms
Every case of PD is unique; some patients
experience different levels of symptoms, and some also have
varying rates of progression of the disorder. Parkinson’s
disease produces primary and secondary motor symptoms as
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Abigail Daniels
well as non-motor effects. Primary motor symptoms include
a resting tremor, which is one of the most significant features
of PD. This shaking that occurs when muscles are relaxed
usually begins in one side of the body and typically spreads
to the other side as the disorder progresses. Bradykinesia, or
slowness of movement, often occurs in patients with PD,
making it appear as if the person has a reluctance to move.
Although the patient has all the inputs and knows what needs
to happen, the signals in the brain are not sent to perform and
control physical functions. Therefore, simple everyday tasks
such as brushing their teeth, can become almost impossible
for patients to manage. Rigidity is also expressed, as patients
seem to appear stiff throughout every action they perform.
This stiffening factor decreases facial expression, upright
balance, and has a tendency to cause problems with the
swallowing function which can result in drooling [5].
GENETIC ENGINEERING AND ITS
MEDICAL APPLICATIONS
Deoxyribonucleic acid (DNA) is the genetic code
that links us to our parents and children and controls the
complex body processes required for daily life. DNA is made
up of long strings containing nucleotide bases, and the
combination of three of these bases codes for an amino acid.
Amino acids are the building blocks for proteins which are
used in every bodily process. When there is a mistake in the
code- whether it was passed down genetically before birth or
actively throughout a person’s life- it is possible that protein
synthesis is altered to either not form proteins at all or to form
malfunctioning proteins. A minor inconsistency in one’s
DNA may not significantly impact the person’s quality of life;
however, when a vital protein is missing or not working
properly, consequences may emerge in the form of
detrimental disorders such as Parkinson’s disease (PD).
There are other symptoms that occur with PD, but
they are not as prominent. Among these, freezing can occurtypically during walking. A patient will be moving forward
and then suddenly appear to have his or her feet glued to the
floor. The reason for this is that the brain signals stop
connecting the movement functions, resulting in immobility
for the patient. Communication through speech and
handwriting also declines. Speech slows and becomes more
difficult for the person, and a stammer may appear [6].
Patients may also show signs of non-motor functions decrease
that include loss of REM sleep, constipation, mood disorders,
loss of smell, and a decrease in blood pressure while standing
[7]. These burdening symptoms hinder a patient from ever
having a normal life on their own again. This strain not only
affects the patient, but also buts emotional and financial
distress on their loved ones and can be passed down through
future generations.
When mutations lead to genetic disorders, there is
sometimes a solution via gene therapy. Gene therapy is the
process of altering DNA to fix a mistake through the
procedure of gene doping, or by using tools such as viral
vectors and gene editing equipment. In general, gene therapy
requires physically rewiring the DNA of the ailing patient to
correct their genetic code. Therefore, when DNA replication
takes place, the genes produced will be made from the
correctly coded DNA rather than the damaged strands [9].
Gene therapy has the potential to make life more sustainable
for people who are burdened with any kind of genetic disorder
now, and in the future. The research and testing that goes on
now gets the medical community closer to providing better
solutions for all kinds of patients in the long run.
Gene doping is an area of gene therapy that can be
used to rebuild lost muscle mass for the aging or injured, but
it has been more commonly used for improving athletic
performance. Gene editing tools such as CRISPR Cas9 are
typically known to “cut out” damaged strands of DNA
[9]. Viral vector gene therapy uses a working section of DNA
to replace a mutated section of DNA. The working section of
DNA is inserted into an inert virus which is then injected into
the patient. This virus then transmits its genetic material into
the surrounding somatic cells which will incorporate it into
their existing DNA, resulting in a cell that now contains a
healthy copy of DNA [9]. Adeno-associated viruses (AAV)
are commonly used as vectors because of their ability to
precisely penetrate dividing and nondividing cells without
causing physical harm to the organism itself. AAVs have
shown to produce accurate results consistently and are
therefore one of the most commonly used viruses in viral
vector gene therapy treatment.
Past, Present, and Future of Parkinson’s Disease
Since ancient times, people have been aware of this
“shaking palsy”. However, only 200 years ago, the disease
was brought to life with an official name in a detailed
publication by James Parkinson in London. With that being
said, people still did not pay much attention to this
degenerative disorder for another sixty years when research
commenced. Although there is rapid growth of development
in this area, to this day, the cause of Parkinson’s disease is
unknown, and therefore it cannot be prevented [8].There has
been no correlation found through hereditary factors, but PD
consistently shows its’ appearance in the latter end of a
lifetime. Although there is no way of stopping or slowing
down PD, treatments are available to help with the symptoms
that affect almost one million Americans. However, since
Parkinson’s disease is progressive, most patients stop
responding to treatment and often need to acquire constant
assistance in order to perform daily routines. Discussed later
in this paper are the many different trials that focus on
creating a more effective treatment for Parkinson’s disease
[3].
Parkinson’s disease is caused by the deterioration of
specific neurons in the brain that produce a vital
neurotransmitter called dopamine. Dopamine is a hormone
that signals the parts of the brain that control motion, and if
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not enough of the hormone is produced, the inflicted person
will experience varying levels of immobility. As the disease
progresses, slight tremors turn into extreme balance and
motor skills issues [14]. Currently, a drug called levodopa is
used to treat PD by providing a new enzyme that
synthetically produces dopamine. However, as the disease
progresses, the drug becomes ineffective because it is harder
for levodopa to reach the striatum- which is an area of the
brain crucial in the motor skills system. This occurs because
through the progression of the disease, the amount of the
enzyme that converts levodopa into dopamine decreases,
creating a resistance to the drug. The use of viral vector gene
therapy could potentially provide a successful way to transfer
the drug to the targeted area due to the size and function of
viruses. Adeno-associated viruses are able to overcome the
developed disease and provide a pathway for levodopa to
remain a source of effective treatment for PD.
Only recently, adeno-associated viruses (AAVs)
became one of the most popular viruses to use for treatment
via viral vector gene therapy. These viruses have found to be
already exposed to over 90% of humans, without harm. This
means that these viruses can travel and replicate throughout
the body when injected without causing harm to most
patients. Adeno-associated viruses are extremely small,
containing only one strand of DNA in the genome, and do not
have a protective envelope around them. The AAV2 virus the most studied strand- has been found to consistently place
itself on the 19th chromosome, making it the only viral vector
to succeed in target specificity, providing that a helper virus
is not present [11].
AAV viruses have shown their ability to affect cells
that can divide as well as cells that don’t reproduce. This
information has proven to be extremely useful because it
means that cells such as neurons can still be affected by these
viruses. The changing of these nervous system cells provides
a way to reproduce the newly transported healthy gene for an
extended period of time before the cell dies without
reproducing [12]. It is consistently difficult to transport
macromolecules such as DNA through chemical and physical
barriers while still remaining site specific. However, AAVs
have shown the possibility of penetrating difficult-to-reach
cells after the injection of several strands of the virus. The
revelation of this possibility provides a way of treatment for
diseases where a surgical procedure would be deemed
impossible. AAVs have shown great effectiveness in studies
of injection into muscle tissue, retinal cells, and cells within
the brain [13].
HOW VIRUSES CAN BE USED AS
TREATMENT FOR DISEASES
Viral Vectors
When a virus attacks the body, it’s genetic material
is injected into cells throughout the body. The new viral DNA
in the cell then replicates instead of the original cell DNA.
This results in codes for more copies of the virus instead of
additional copies of the healthy cells. Typically, these agents
are seen as harmful, but as new discoveries arise, the viruses
can be seen as potential cures or treatments for diseases.
Because viruses transport genetic material, there is a potential
that they can become one of the best forms of drug
delivery. In order to use viruses as vectors, or deliverers, of
gene therapy, the original DNA in the virus needs to be
removed from the agent so the replacement DNA can take
over. Once the new virus is injected into the body, the targeted
cells then produce more copies of the healthy gene, and the
old, mutated strand of DNA is no longer replicated [9].
The use of AAVs as viral vectors has great promise
to the medical world due to the abundance of benefits and the
very limited drawbacks. There currently remains a chance that
the viruses could not travel to the desired area and infect
unintended cells throughout the body. Another risk comes
with the inability to automatically stop replication of these
viruses once they start. This can create a dangerous
overabundance of the DNA being displayed to code for
proteins. These viruses have shown unwavering results of
target specificity and has proven to be extremely effective in
transporting new strands of DNA, while sustaining the effects
for a long period of time. Since most humans have already
been exposed to adeno-associated viruses, when an AAV is
injected into the body, antibodies are not made, providing
easy transportation of the virus and long term effects of the
new DNA. Because adeno-associated viruses are so small,
they are successful in overcoming cellular barriers, but they
are limited to the amount of DNA that they can provide.
Because of this, more production of the virus will be required,
which shows its difficulty as well [11]. Although there are
downsides to using AAVs to treat medical disorders, this way
of gene therapy gives much promise to improving the quality
of lives in the future. The better understood the AAVs are
Although the first gene transfer system was recorded
in 1983, the first successful viral vector was established
around 1990. Ever since then, there has been an abundance of
testing to determine and surpass the complications that come
with this form of gene therapy. Viral vectors have proven to
be difficult to control since they are extremely small and
because they are biological material, which means that they
don’t always act according to plan. After two decades of
testing, results have shown that viruses have consistently been
able to transport any new gene implanted into their system.
Research has also shown that certain strands of DNA work
better with some viruses than others. This information,
therefore, produces different results in effectiveness and rate
of reaction during trials. Although using viruses as vectors
proves to be a very complex, challenging realm, it holds much
potential for our future health [10].
Adeno-Associated Viruses
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now, the more use they will be to treating symptoms and/or
curing diseases for future generations.
remove any harmful nature, and it is most likely already in the
patients’ bodies so there is little chance of rejection to these
new vectors.
Below is an image of an AAV2 genome map (figure
2). The genetic material in an adeno-associated virus can be
divided into two groups based on functionality. The first
group depicted in blue is the the set of base pairs in AAV2
devoted to the replication of the virus. As mentioned above in
the section describing the use of viruses in the treatment of
diseases, AAV2 replicates at increasing rates when a helper
virus is present. The replication base pairs are injected into
the host cell which then creates more AAV2 and then
subsequently lysis, or disintegrates [18]. This behavior is
closer to that of a pathogenic virus and is not desirable for
viral vector gene therapy. The gray base pairs are the second
group and they code for the protein shell that makes up the
actual physical appearance of AAV2 [18]. Since the Rep base
pairs are the ones that are actually injected into host cells and
are incorporated into their DNA, they are the ones that
researchers are interested in. When new genetic material is
spliced in, in the form of more base pairs, it too becomes part
of the host cell’s DNA [18].
GENETIC MODIFICATION OF ADENOASSOCIATED VIRUSES TO TREAT PARKINSON’S
DISEASE
Current Treatment of Parkinson’s Disease
The most common treatment for Parkinson’s disease
is a drug called levodopa [3]. When PD begins to take its toll
on the substantia nigra and the brain becomes less capable of
creating dopamine, levodopa is used to fill that gap [3][14].
When the body needs to produce more dopamine, first an
amino acid called L-dopa must be made. Neurons in the
midbrain express a gene to create aromatic L-amino acid
decarboxylase (AADC), an enzyme that transfers L-dopa into
more dopamine which is received in another part of the brain
called the putamen. This influx of dopamine allows the brain
to re-establish motor function [3]. levodopa is a clinically
proven way to ensure that there is enough L-dopa in the
system to manufacture enough dopamine for normal bodily
functions even when the person’s body has a declining
amount of proper neurons and enzymes [15]. levodopa,
however, is not a permanent solution; It can help when there
are still some AADC enzymes to turn it into dopamine, but as
PD continues to cause degenerative issues in the brain, these
enzymes become more and more of a limiting factor [3].
New Possible Treatment And How It Works
For the last four years Voyager Therapeutics has
been in human trials for a new therapy to remedy this decline
in dopamine production [16]. Voyager Therapeutics is a
company devoted to developing genetic therapies for diseases
in the central nervous system. The company is based in
Pittsburgh and are currently researching a pathway to get
around the deterioration of the substantia nigra by skipping it
all together [16]. While PD is very damaging to certain areas
of the brain, one area that it seems to have little effect on is
the putamen, the location of the dopamine receptors.
Unfortunately, there are not many AADC enzymes in the
putamen, so this will most likely prove a difficult venture for
Voyager Therapeutics [3]. The drug that Voyager
Therapeutics is testing would hopefully increase the number
of AADC enzymes in the putamen, allowing it to both
produce and receive dopamine, thus returning the former
function of the dopamine pathway.
FIGURE 2 [18]
Depicts the function of the 4,680 base pairs in AAV2
Voyager Therapeutics is not the first to use AAV2
for these reasons. Pharmaceutical companies, such as GSK
are also working on incorporating AAV2 in gene therapies
[19]. The real innovation comes with the second part of this
treatment - The gene for which AAV2 is a vector, is called
hAADC, which when expressed, produces the AADC
enzyme. This combination of viral vector and gene is to be
administered to the putamen. Once in position, cells in the
putamen will have the ability to express hAADC and create
the AADC enzyme. Dopamine can then be produced in the
same area of the brain that receives it, avoiding the
deteriorating substantia nigra and creating an all-around more
efficient dopamine pathway.
The specific treatment that Voyager Therapeutics
has created is a viral vector transport called VY-AADC01.
The viral part of this viral vector is a virus called the AAV2.
AAV2 acts slightly atypically from normal viruses, causes no
immune system reaction, is not a pathogen, and, according to
Voyager Therapeutics, is a virus, “to which >90% of humans
have been exposed” [17]. That is the genius of using AAV2.
This viral vector does not require any reprogramming to
Benefits of New Treatment
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Voyager Therapeutics is still in the human trial
phase of their breakthrough treatment, but they have been
testing VY-AADC01 since 2013. On December 7, 2016
Voyager Therapeutics gave their interim results for the phase
1b testing they had been conducting for the past three years.
Phase 1 means that they are mainly testing the safety of
increased levels of dosing with VY-AADC01, but because
they are testing on patients who are in advanced stages of PD,
they have also collected data on the effectiveness of their
drug. Patients were asked to keep journals recording when
they were on and off dosing, and when they experience
trouble moving. Researchers also utilized the Unified
Parkinson’s Disease Rating Scale III (UPDRS III) to analyze
their results. This scale aims to determine the extent to which
one is affected by PD and has 31 categories from speech to
posture. Each category is ranked from 0 to 4, 0 being the least
impact on that category and 4 being the most. Using the
reports from each patient and the UPDRS III, Voyager
Therapeutics researchers noticed that “treatment with VYAADC01 resulted in a 14-point, or 44%, improvement in
UPDRS-III off medication, a 9-point, or 55% improvement in
UPDRS-III on medication” [16]. This is great news for the
improvement of advanced PD as it would enable sufferers to
live with more control over their own bodies and more
independence in their lives overall. However, that is not all
that Voyager is hoping to improve with their trials. They are
also working on ways to make the administration process
more efficient, quicker and safer.
have to be monitored before, during, and after administration
to ensure that there are no helper viruses present.
FIGURE 3 [21]
Depicts the life cycle of AAV in the body with the
presence of a helper virus.
Another area in which safety is of huge importance
in this procedure, is the actual administration of the drug. The
viral vector carrying the hAADC gene is injected directly into
the putamen. This can be dangerous as the putamen is very
close to the center of the brain, and any inaccuracies in the
injection site could be detrimental. To remedy this,
researchers at Voyager Therapeutics are aided by magnetic
resonance imaging (MRI) which provides them with real time
images of the brain throughout the procedure [16]. This not
only allows for accuracy of the injection, but could also cut
down on total time in surgery. It is also important for these
researchers to make sure they are performing each dosing in
the most efficient and safest way possible, so it is their duty
to find ways to improve their surgical technique and limit any
negative side effects in their patients.
PAVING THE WAY FOR GENETIC
ENGINEERING
Ethical Considerations of AAV2 Treatment
When a new treatment, especially one involving
surgical procedures and injection of viruses, is being tested,
there are ethical issues that have to be taken into
consideration. The biggest issue people often have about viral
vector gene therapy comes from concerns about safety. A lot
of testing needs to be done to ensure the health of patients
involved in viral vector studies because of the wide range of
inflammatory immune responses that different viruses can
cause [20]. These responses can be especially dangerous for
the elderly, and those with weakened immune systems, such
as in people with PD. This is less of an issue with AAV2
because of its relatively nonpathogenic nature and high rate
of appearance in the population [3]. However there are still
some cases, like if the patient has certain preexisting
conditions, where this virus could possibly be very harmful.
Below is an image of two possible life cycles for AAV2.
When AAV infects a cell and there are no helper cells present
in the body, AAV’s viral genes are dormant. However, when
there is a co-infection of Adenovirus, the AAV virus goes into
productive infection stage, where the viral genes become
active, and the host cell begins creating new AAV cells. For
this reason, the health of patients taking this new drug will
Improving the Innovation
As these trials go on, Voyager Therapeutics is
working on ways to improve their own procedure. They are
still in human testing phase 1 but they are planning to move
int o placebo trials by mid 2017 and are swiftly on their way
towards FDA approval for commercial use. One way that they
are trying to improve treatment is through varying angles of
administration of VY-AADC01 to the putamen. Researchers
at Voyager Therapeutics believe that administering doses
through the occipital lobe in the back of the brain could be
one way to improve results. By dosing through the back of the
brain, there is a more direct path to the putamen. This more
direct dosage could lead to better deliverance of the drug and
a better coverage of the putamen all around. If this technique
proves successful, it could mean fewer doses necessary and
shorter surgery times [16]. This is a very important
development to make, as factors like old age and
complications during surgery can lead to significantly higher
mortality rates [22]. Quicker and more efficient surgeries lead
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to fewer chances for mistakes and fewer deaths from
complications. Another way Voyager Therapeutics is
attempting to improve their procedure is through some extra
preventative procedures. One patient in their phase 1b trials
experienced some complications during surgery that resulted
in a blood clot and subsequent arrhythmia. Researchers made
sure to add a surgical protocol to prevent any such incidents
from occurring and no further complications were seen [16].
Besides the continuous work to make this procedure as safe
as possible, this drug being effective after only a single use
and the success of these trials hopefully leading to VYAADC01 becoming a common treatment, makes the future of
patients with PD look very bright.
coming in right behind. The benefit of non viral vector gene
therapy over viral is that there is a drastically reduced rate of
inflammatory immune reactions. This is highly desirable and
any advancements in either form of gene therapy brings us
closer to getting the best of both methods. Voyager
Therapeutics’ success with AAV2 is another step in bridging
the gap between efficiency and safety.
Making Life Sustainable Through Viral Vector Gene
Therapy
Sustainability can technically be defined as the
“human use of resources which preserves the environment so
that human needs can be met also by future generations,” [23].
However, different applications of that definition can change
depending on the topic of discussion. For example, a
computer engineer might have a focus of designing programs
that are useful for current and future generations, whereas a
chemical engineer might work on designing products that are
harmless to the environment. In the medical world,
advancements usually focus on sustaining the quality of life.
This allows doctors treating a human being suffering from an
unfortunate disease, injury, or other mishap, to improve their
condition by either alleviating the symptoms or fixing the
problem all together. After the new technology is introduced
to the patient, if it does in fact sustain the quality of life, the
patient will no longer struggle immensely, but have much
more ease in their everyday life, enabling them to enjoy things
in a way they may have never thought possible. This provides
tremendous help for current generations, and could also
support future generations as well. For example, a mother
could raise her children better if she is not otherwise occupied
with taking care of herself and struggling to perform normal
functions.
Possible Future Developments
In the long run, the success of these trials may prove
the effectiveness of AAV2 as a viral vector. Another benefit
of AAV2’s success in this trial is its use in future treatments.
Currently, Voyager Therapeutics is developing a treatment
for Alzheimer's Disease utilizing an adeno- associated viral
vector, giving AAV2 even more chances to prove itself. As
mentioned above, Voyager Therapeutics is not the first
company to work with this virus, and as more and more
companies experiment in gene therapy, AAV2 may become a
standard in the field of medicine, helping to cure many
varieties of genetic diseases and disorders. With that end in
mind the there are some areas where gene therapy could
develop more as a field.
One way to improve viral vectors in general is
through the use of transgene promoters, which regulate when
and where the new gene is active after it is brought in through
a viral vector [20]. Viruses are not always the most effective
gene transporters, and even when they are successful, there is
no guarantee that the gene is taken up in the tissue and
expressed correctly. The research of transgene promoters for
viral vectors could lead to discovering how to make them even
more efficient.
Throughout the aftermath of inventing new medical
technologies comes the focus of sustaining economic
resources. It is typically known that new procedures or drugs
are extremely expensive, and can cause a huge financial
burden on patients and their loved ones. For those who are
wealthy, this might not be a concern for them, and they have
access to the best technologies in the world. However, the
majority of Earth’s population does not have sufficient funds
to pay for all the high end medical treatments. Another factor
that comes with producing innovative advancements is
discovering how to allow the population to benefit from the
new developments fairly. This means providing ways for all
patients to have access to treatments without creating the new
kind of stress that involves their finances that could
potentially just be passed down onto future generations.
Engineers invent new technologies in order to solve problems
in the real world through applications of theoretical
knowledge. When working on a new project, all engineers
must discuss the sustainability aspect and how it can benefit
the world now and in the future. Bioengineers using viral
vectors have the goal of giving current patients better lives,
Another possible avenue for viral vector gene
therapy is the research and testing of different stereotypes of
the adeno-associated virus. So far, AAV1, AAV2, AAV5,
AAV7, AAV8, and AAV9 have all been researched and used
in gene delivery studies [18]. The work that Voyager
Therapeutics is doing with AAV2 is just part of discovering
the best variety of adeno-associated virus and determining
which could be best to use in different situations. The success
of AAV2 for the treatment of PD means that we know just
that much more about how to use these viruses and how much
they can help to develop the field of gene therapy.
One last way that viral vector gene therapy in general
can be of use to the field of medicine is by helping researchers
in the medical field determine how to mirror their properties
onto non viral transport systems [20]. Viral vectors are some
of the most effective methods for gene therapy known to
science with non viral methods of treatment like vaccines
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and also providing more effective treatments so the people of
future generations have more quality lives as well.
putamen, thus restoring the dopamine pathway along with the
use of the current treatment levodopa.
Voyager Therapeutics have successfully begun
human trials on using adeno-associated viruses to transport
genes that code for a missing enzyme that enables effective
drugs to be used to treat Parkinson’s disease [16]. This means
that the theoretical concept of using viral vectors as a way of
gene therapy has become a practical application to benefit
people today. Since much progress has been made on this
development, drawbacks have also been discovered that
reduce the sustainability factor. It has been noted that by
using viruses as vectors there comes a risk of infecting
unwanted cells. If a virus carrying a new gene accidentally
infects a patient's’ reproductive cells, then that patient will not
receive the benefits of the new DNA due to lack of
propagation throughout the body that would affect other types
of cells. Instead though, the DNA of that patient’s offspring
could become mutated due to the new gene that was forced
in. The children would then have potential, genetic dangers
that could come about from the unnatural addition of
unnecessary DNA; however exact conditions have not been
revealed through testing yet.
There are still hurdles to get over and places for improvement,
but as Voyager Therapeutics’ researchers work toward the
success of their drug, they are also working toward the
success of viral vector gene therapy. Gene therapy is
relatively new, so while AAV2 could be the biggest
achievement for the treatment of Parkinson’s Disease since
the discovery of levodopa 40 years ago, it will also set a great
precedent for viral vectors in general as viable treatments for
genetic diseases.
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Although this a risk comes with serious fallbacks,
scientists have worked on minimizing this risk to provide
insurance of the treatment for all patients [12]. Since human
trials are still going on, this treatment has not been made to
the public. Therefore, costs of the advancement have not been
sufficiently analyzed and set into place for public use.
Although clinical trials have not been fully completed,
progress reports have been released by Voyager Therapeutics.
All original surgeries were successful and over the past six to
twelve months, patients have reported a decrease in
dyskinesias- their impaired movements- throughout their days
by 1.1-2.2 hours per day. Researchers have also reported a
42%-56% increase in effectiveness of current treatment of the
drug due to the newly synthesized enzyme making it capable
to be used. Lower dosages of the medication required have
also been noted [16]. Although there is still much to find out
about this treatment, there is great promise in providing
sustained life for patients with PD by using adeno-associated
viruses, as seen in the positive interim results.
REVIEW OF AAV2 AS A TREATMENT FOR
PARKINSON’S DISEASE
Parkinson’s Disease impacts thousands of people
and their families nationwide every year. The cause of PD is
not fully understood yet, but the immediate conditions such
as loss of motor function, and mood disorders can be
explained by the decline in dopamine production. Voyager
Therapeutics is currently studying the effects of their new
viral vector treatment for PD as they establish its safety in
large doses. Their treatment involves the non-pathogenic
virus AAV2 and the hAADC gene to be applied to the
7
Michael Kassabian
Abigail Daniels
01.06.2017.http://www.genetherapynet.com/viralvectors/adeno-associated-viruses.html
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l
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&p=irol-newsArticle&ID=2228332
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03.22.2017 http://www.mdpi.com/2071-1050/4/12/3234/htm
ACKNOWLEDGEMENTS
We would like to thank our co-chair, Mikayla
Ferchaw, for the time that she has dedicated to our paper, as
well as helping to mentor us as first year engineering students.
Our chairs, Anthony Pulleo and Suyesh Acharya, have been
extremely helpful in guiding us along the path to the
conference, which we are very grateful for. We appreciate all
the comments and direction that has been provided by our
writing instructor, Janet Zellman. We’d both like to also thank
our high school biology teachers for sparking our interests in
this area.
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