Those of us in the Biomedical Science Master’s program at
Regis University where this post originates have spent the first quarter of the
semester looking at lysosomal storage disorders including Parkinson’s
disease. Shachar et al. (2011) describes
a causal relationship between these two diseases where mutations in the
glucocerebrosidase gene caused by Parkinson’s disease results in an enzyme
deficiency consistent with Gaucher disease, the most prevalent lysosomal
storage disorder. The main focus of our
investigation of lysosomal storage disorders including Parkinson’s disease has
been on gene therapy trials using murine models. The current success in treating these
diseases in the murine model and non-human primates is high and promising,
however there is a large contrast in the success of treating these diseases in
human subjects.
Parkinson’s disease is the second most prevalent age related
neurodegenerative disease with an average onset occurring close to 60 years of
age, although early onset can occur. The
symptoms of the disease most commonly include tremor, rigidity, bradykinesia,
and several non-motor symptoms more commonly associated with cognitive
functioning (Douglas 2013). Rush
University Medical Center (2013) describes two methods currently being used for
treating Parkinson’s disease in humans which include symptomatic therapies and
protective therapies. Symptomatic
therapies focus on supplementing dopamine because the natural release of
dopamine by cells is affected by the disease, many drugs fall into this
category and have been available for many years to treat individuals with
Parkinson’s disease. Protective
therapies work to delay the degenerative processes occurring in the brain and
are largely focused on gene therapies, these treatments are currently only
available to human participants in a handful of clinical trials.
The success of treating Parkinson’s disease has recently hit
the media with the full time return of Michael J. Fox to our television sets who
postponed his acting career in 2000 because of his worsening symptoms of
Parkinson’s disease. His doctors have
recently been able to find the right balance of medications and dosage levels
that work for him. While the exact
treatment regimen used by Michael J. Fox is between him and his doctors, it is
most likely through the use of current symptomatic therapies. It is important to note that symptomatic
therapies are not a cure for Parkinson’s disease and they are only able to mask
the symptoms of the disease for some time.
Symptoms of Parkinson’s disease are typically measured by
the Unified Parkinson’s Disease Rating Scale, UPDRS (Kordower and Bjorklund
2013), which rates symptoms from zero to four with a score of zero representing
normal functioning and a score of 4 representing severe impairment. This rating scale can be used to measure both
“on” and “off” scores. “On” time is
considered the period where therapies are successful in treating the symptoms
and improving motor control with the right balance of dopamine supplemented to
the system. “Off” time is considered the
period where the amount of dopamine being supplemented is out of balance and symptoms
worsen, this can occur during the initial assessment of the appropriate dosage
of dopamine which is highly variable per individual and as the effects of the
drug where off which will typically occur after some time of the drug being
effective. Current symptomatic therapies
are continually being improved to increase the amount of “on” time an
individual experiences from the drugs and dosages are continually monitored by
the prescribing doctors.
The most common symptomatic therapy is focused on increasing
dopamine production within the nigral neurons and is accomplished through drugs
like Levodopa and more often Levodopa in combination with Calbidopa (Douglas
2013). Levodopa targets the remaining
nigral neurons that are still exhibiting proper functioning to increase
dopamine production. The first two years of Levodopa therapy on treating
Parkinson’s disease shows large success in controlling the symptoms of the
disease, however after this time the drug can show a wearing off effect and
symptoms once masked by the therapy tend to return (Rush University 2013). Following the wearing off effect of Levodopa
dopamine agonist, Pramipexole and Ropinirole, along with COMT inhibitors,
Entacapone and Tolcapone, can be used to increase delivery of Levodopa to the
brain and decrease the breakdown of Levodopa (Rush University 2013). Other symptomatic medications are available
that work through similar mechanisms.
A second symptomatic treatment option for individuals with
Parkinson’s disease is deep brain stimulation, referred to as DBS. While the exact target within the brain is
still widely debated, DBS is a surgical treatment that places an electrical
wire into the brain tissue and high frequency stimulation is delivered through
a small battery pack that is placed under the skin near the thoracic cavity
(Rush University 2013). DBS works by
inhibiting glutamate release within the cells of the subthalamic nucleus
(Douglas 2013). This treatment is most
often reserved for those individuals who show little improvement with
symptomatic drug therapies. While both
DBS and combination drug therapies can work well to reduce symptoms of the
disease for some time the future for treating Parkinson’s disease lies with protective
therapies that aim to actually stop and reverse the effects of the disease on
neurons within the CNS.
Current research being conducted on protective therapies is
focused on gene therapy and stem cells.
The association of many mutated genes with Parkinson’s disease has been
researched and includes, among many others, the PARK1 locus which encodes for
alpha-synuclein, several autosomal recessive genes and proteins including
Parkin, PINK1, DJ-1, and an autosomal dominant gene, LRRK2, which is the most
correlated gene mutation found within individuals with Parkinson’s disease
(Douglas 2013). Protective therapies aim
to stop and reverse the damage to the brain caused by Parkinson’s disease
through introducing new stem cells to the affected areas of the brain or by
introducing viral vectors that can deliver new functioning genes. Although these therapies show positive clinical
significance in the lab with both mice, rat, and non-human primate models,
trials on humans have proven to be less effective. The discrepancy of the effectiveness of
treatment is related to both the blood brain barrier and general difficulties
accessing the affected areas of the brain while delivering the therapy.
Several studies investigating the effects of glial cell line
derived neurotrophic factor, GDNF, have found that protection and restoration
of neurons in animal models was possible.
Clinical trials in humans were conducted by Nutt et al. (Kordower and
Bjorklund 2013) and used infusions of recombinant GDNF proteins that were
directly administered into the lateral ventricles through mechanical pumps. However
the double blind study did not produce any significant results and a number of
side effects of the treatment were reported.
A postmortem autopsy revealed that the GDNF was unable to diffuse out of
the lateral ventricles and therefore unable to have an effect. A second open label study used a similar
method but injected the GDNF directly into the postcommissural putamen which
showed promising results in phase I clinical trials and improvement of motor
symptoms by about 33% were seen. PET scans revealed increased fluoradopa uptake
after about a half year of treatment. However when taken to phase II clinical trials
no significant benefit was seen and antibodies towards GDNF were found along
with an identified risk for cerebellar damage that caused early termination of
the trial (Kordower and Bjorklund 2013).
Other methods of delivery of GDNF proteins have been
developed but have been yet to see human trials. These include genetically engineered cells
that are encapsulated in a semi-permeable membrane that can be delivered to the
brain and avoid detection by the immune system while delivering therapeutic
agents to the cell (Kordower and Bjorklund 2013). Brendan Harmon from Northeastern University (Science
Daily 2013) has also developed an intranasal approach for delivery of GDNF to
the brain that is able to pass the blood brain barrier that may create a
noninvasive method for delivery of therapeutic agents to the brain. This method has proven to be successful in
rat models but has not yet seen human trials (Science Daily 2013).
Other human trials investigated the use of adeno-associated
virus vectors to deliver NTN to the brain, NTN is similar to and works in the
same way as GDNF (Douglas 2013). This AAV2-NTN technique showed an 80% improvement
level that lasted for up to 12 months following administration in Rhesus
monkeys. However when taken to clinical trials
in humans complications in the delivery to the brain during surgery resulted in
one death and other individuals who underwent successful surgeries showed
several major side effects. Despite
these complications results were promising and this method was taken to a phase
II clinical trial but again no significant results were found using human
subjects after one year (Douglas 2013). A
follow up study did find significant results after 18 months which may suggest
that the procedure was a success but may need more time to work and show
corrections within human subjects, further trials with longer follow up times
is under way.
Within the dopaminergic biosynthetic pathway dopamine is
converted to another molecule known as AADC and AADC has been used therapeutically
to reduce Parkinsonism symptoms. Adeno
associated vectors using AADC have reached Phase I clinical trials and motor
improvements up to 75% have been seen (Douglas 2013). Outweighing the clinical success of the
AAV-AADC many patients within the sample developed brain hemorrhages which were
related to the surgery delivering the AAV.
A follow up to this particular study was performed and it was found that
the positive effected waned after a one year period (Douglas 2013).
AAV vectors using CERE-120, which encodes for Neurturin,
also known as NTRN, have also reached Phase II trials in humans based upon
highly positive results in monkeys (Kordower and Bjorklund 2013). Phase I trials using this vector again showed
positive results although no significant difference was found to exist between
low and high dosage groups but very few side effects were reported. Given the low amount of side effects the
AAV-CERE-120 vector reached Phase II clinical trials but again showed no significant
results with only limited clinical benefit (Kordower and Bjorklund 2013). Interestingly a follow up study did show more
significant results after 15 and 18 month periods again suggesting that longer
treatment follow ups may be necessary.
The first successful Phase II clinical trials seen in humans
was with a gene therapy known as NLX-P101 which significantly reduced motor symptoms
(USA Today Magazine 2012). This treatment
used glutamic acid decarboxylase, known as GAD, was injected into the brain
using a virus vector. GAD is able to
produce GABA which is an inhibitory neurotransmitter that is able to decrease
the firing of neurons. So while dopamine
loss within the brain is most often associated with the major mechanism of the
symptoms of Parkinson’s disease a decrease in GABA is also seen. By reintroducing GABA into the brain the
dysfunction of the circuitry responsible for motor coordination can also be
reduced (USA Today Magazine 2013).
In summary new methods for treating Parkinson’s disease are
being developed and tested and the results are promising. Both mouse and rat studies along with studies
on non-human primates have produced significant data that at the very least
gives hope in reducing and eliminating the effects of Parkinson’s disease on
the brain. However transferring the
success of these trials to human trials have proved to be difficult for several
reasons including the inability of therapeutic agents to cross the blood brain
barrier and difficulties of surgical methods used to directly deliver the therapeutic
agents to the correct regions of the brain.
The future for an individual diagnosed with Parkinson’s disease is
getting better every day, with increased efficacy of symptomatic drugs that
able to mask the symptoms for several years and the advancement and success of
therapeutic drugs in correcting the effects on the brain gives hope that
someday a cure for Parkinson’s disease may be found.
References
Douglas MR.
2013. Gene therapy for Parkinson’s
disease. Expert Rev Neurother. 13(6): 695-705
Federation of American Societies for Experimental
Biology. 2013. Science Daily. A noninvasive avenue for Parkinson’s disease
gene therapy.
Kordower JH, Bjorklund A. 2013. Trophic factor gene therapy
for Parkinson’s disease. Movement
Disorder Society. 28(1): 96-109
Rush University Medical Center. 2013. Clinical Services Parkinson’s disease. Chicago
USA Today Magazine.
2013. Gene therapy reverses
symptoms. The Society for Advancement in
Medicine. McLean, VA.
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