Stem Cell Transplants Treat Alzheimer’s and Parkinson’s disease

Abstract
Alzheimer’s disease is a type of dementia, while Parkinson’s disease is known as a debilitating neurodegenerative disease that affects significantly more men than women. The two disorders have some similar symptoms but are also very different. With regards to treatment, no standard intervention has been developed for the treatment of Alzheimer’s disorder. The only existing drugs are those that address some of the symptoms. Likewise, there is no standard therapy for those with Parkinson’s disease. But lifestyle changes, approved drugs, and surgical operations can be recommended to address symptoms. Nevertheless, stem cell research has shown a lot of promise in helping to restore and regenerate destroyed brain tissues and is, therefore, currently being tested to help treat brain disorders such as Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. This work looks at what the evidence is saying about the efficacy of stem cell transplants approach in the treatment of Alzheimer’s and Parkinson’s diseases. It also investigates the possible drawbacks of using the approach.
Introduction
Expectations from medical researchers to come up with a breakthrough treatment for the most widely-occurring neurodegenerative ailments in the French population, namely, Parkinson's Disease (PD) and Alzheimer's Disease (AD), which impact nearly 200,000 and 900,000 individuals, respectively, are now higher than ever before. Considering the nation's aging population, these figures are expected to continually climb, with around 1.3 million persons expected to be diagnosed with Alzheimer's by the year 2020 (Alzheimer’s Association, 2015). PD represents a neurodegenerative ailment that is marked by dopaminergic neuron degeneration within the pars compacta area of the brain's substantia nigra (Hwang, Gill, Pathak, & Subramanian, 2018). The degeneration occurs due to dopamine-generating nerve cell degeneration within the substantia nigra, which is a mesencephalon area responsible for controlling movement. The degeneration leads to lower levels of neurotransmitter, dopamine, within the patient's brain, vital to body movement regulation.
Parkinson's' clinical symptoms emerge when roughly 70 percent of neurons that produce dopamine get damaged. They include bradykinesia (or a slowing down of physical movement), tremors or shaking, muscular rigidity or stiffness, pain, and impairment in coordination and balance (i.e., postural instability). Disease prevalence is approximately 1.5 times more in males as compared to females; further, PD rates grow with age, with the disease impacting around one to two percent of individuals aged above 70 years. While its causes are yet to be determined, several research scholars claim the disease emerges as a reaction to non-genetic and genetic elements combined (Goodarzi et al, 2015).
Alzheimer’s has been deemed to be one among the commonest causes underlying dementia. In spite of many decades' worth of studies on the disease, a standard Alzheimer's-modifying treatment is yet to be devised, with the medications presently approved being able to only provide symptomatic relief to patients (Bali, Lahiri, Banik, Nehru & Anand, 2017). Roughly 5.3 million citizens of the US suffer from Alzheimer's, of which 5.1 million belong to the above-65-years age group. The remainder, aged below 65 years, have premature disease onset. By the year 2050, it is estimated that Alzheimer's patients in the nation will rise by as much as ten million; this growth has largely been ascribed to the aging of the baby boomers. At present, it is estimated that every 67 seconds, Alzheimer's develops in yet another individual (Alzheimer’s Association, 2015).
Several brain neurons gradually start degenerating, particularly in the hippocampus, which is the site of storage of short-term memory; the degeneration progressively spreads throughout the individual's brain. The tau and amyloid-? peptide proteins are considered responsible for the degeneration. The latter, a naturally-occurring protein within the human brain, builds up until senile or amyloid \\\"plaques\\\" are formed. This accumulation proves harmful to nerve cells. Additionally, it is linked to modifications in the tau protein that is involved in neuron structure. Consequently, brain neurons get disorganized, resulting in cell death and neurofibrillary degeneration. The above extremely slow process of neurodegeneration starts impacting a patient's brain several years prior to the emergence of the earliest disease symptoms (The Research Journal, 2017).
Stem Cell Transplants and PD
As of now, there is no standard intervention for PD; the existing approved medicines and interventions are for reducing the symptoms. Existing interventions include the oral administration of dopamine receptor agonists and L-DOPA (L-3,4-dihydroxyphenylalanine). Deep brain stimulation of the globus pallidus and the subthalamic nucleus utilizing electrodes is also a known intervention to address the symptoms of PD. The pharmacological intervention mentioned above is based on L-DOPA uptake and the blocking of the degradation of dopamine utilizing dopamine agonists. Many hospitals make use of dopamine receptor agonists to L-DOPA starting. Moreover, the agonists are regarded as useful in the later stage of Parkinson’s disease as a complementary therapy in conjunction with L-DOPA. The stimulation of dopamine receptors at both the pre and post synaptic ends is their mode of action. Levodopa is an example PD medication. It is utilized to treat PD by relieving dopamine deficiency effects. However, the therapeutic effect of the drug after three years reduces considerably (Goodrazi et al, 2015).
There are several drugs used for the treatment of Parkinson’s disease. They include Amantadine, monoamine oxidase B inhibitors, anticholinergic drugs, Ropinirole, Prmaipexole, and Bromocriptine. Some of the above medications, e.g. Amantadine, treat PD by stimulating the region of the brain affected by it (16, 17). Monoamine oxidase B inhibitors work by stabilizing the levels of dopamine in synaptic cleft. Different stem cells are being researched as of now to use in the cellular treatment of neurological diseases such as PD, stroke, multiple sclerosis, and spinal code injury. Those being researched for curing PD are yielding positive results. Both their benefits and drawbacks are being considered (Goodrazi et al, 2015).
Stem Cell Transplants and AD
As of now, there is no agreement as to how to precisely diagnose and how to monitor Alzheimer’s disease. The lack of uniform diagnosing and monitoring methods has hindered the development of effective AD cures. Existing treatments for the disease include the prevention of neurotransmitter degradation. This is known to offer a temporary relief against AD’s main symptoms but it does not address AD’s pathophysiological burden. Cell stem studies have been done to investigate if stem cell transplants can help to replace the damaged neurons in people with AD or if they can secrete known trophic features to protect cells. Blurton-Jones et al. investigated if stem cells transplants of neural nature can reverse memory impairment. To investigate neural stem cells and how they could help with cognitive functions and Alzheimer’s pathology, the cells were transplanted into mice and they revealed that they can reduce the loss of memory and spatial learning. The stem cells also boosted synaptic density helping to reduce the symptoms further (Bali et al, 2018).
However, there are some studies that have concluded that the use of transplanted cells activate an immune-modulatory response that, in turn, causes cytokines secretion and release. This may target the underlying pathology of AD. A pharmaceutical research company – Neuralstem, Inc. – recently released comprehensive data on the success of stem cell transplants in mice. According to the results and the discussion, HK532: IGF1 (NSI-532.IGF) cells improve memory in mice with AD and reduce spatial learning degeneration. For the purpose of generation a human IGF1, the company engineered a cortical neural cell for transplant. IGF1 cells are known for their neuro-protective properties. It is important to note that the cells were administered in the peri-hippocampal area and it lasted for 10 weeks. It is also important to note that the stem cell transplants used helped to control mice for up to 14 weeks. It would therefore be logical to state that early studies are showing that AD can be used thoroughly and successfully to deal with AD (Bali et al, 2018).
Types of Stem Cells
The stem cells of certain tissues contribute significantly to regeneration, since they are able to divide with ease, replacing dead cells. According to scientists, knowledge of the working of stem cells can potentially aid in devising treatments for heart ailments, diabetes, and other health issues. Stem cells show great promise when it comes to the formulation of novel therapies. Currently, scientists have been using stem cells to develop and test new medicines. The widely-used stem cell form is induced pluripotent stem cells. Medical researchers are able to extract stem cells of adult subjects from multiple tissue types, including blood vessels, brain, liver, bone marrow, teeth, skeletal muscle, gut and skin. Amniotic fluid possesses stem cells. A large number of expectant mothers are now opting for amniocentesis examinations to check for any congenital disabilities in the developing fetus (Railton, 2019).
ESCs or embryonic (pluripotent) stem cells. Their origin lies in a blastocyst's internal cell mass. These cells possess the ability of differentiating into any kind of body cell (like nigral dopaminergic neurons). Human ESCs form one of the dopamine neuron sources for PD-linked transplantation. ESC-derived dopamine neurons are proven to cause functional recovery following transplantation into PD striatum within animal models. But major concerns exist, pertaining to their use in treating neurodegenerative ailments like PD. Among the biggest avoidable side-effects through prolonged differentiation, cell sorting, and in-vitro exhaustion prior to transplant is tumor formation (Goodarzi et al, 2015).
MSCs or mesenchymal stem cells. These are multipotent stem cells capable of commonly being isolated from the bone marrow. This form of MSCs have been most widely research. MSCs may be derived from other sources as well, including the umbilical cord, peripheral blood, dermis, and adipose tissue. They are able to self–renew and differentiate into various cells like dopaminergic neurons, neurons, osteoblasts, myocytes, chondrocytes, adipocytes, and fibroblasts. Further, they provide protection to damaged tissues and facilitate generation of a broad cell spectrum (e.g., dopamine neurons) that can renew lost or damaged cells among Parkinson's patients (Goodarzi et al, 2015).  
Limitations and Risk Factors involved in Stem Cell Transplants
Treatment using stem cells is a swiftly evolving field, with a large number of clinical trials commenced to examine progenitor/stem cell employment in treating cancer and degenerative illnesses, and in repairing lost or damaged tissue. In spite of displaying tremendous potential, innumerable questions persist with regard to its safe application (Herberts, Kwa & Hermsen, 2011). NSCs (neural stem cells) and ESCs have proven to be major transplantation candidates for neurodegenerative ailments, but certain limitations exist with respect to their use (for instance, potential cell regulation issues, tumorigenicity likelihood, and ethical challenges). Meanwhile, numerous research works reveal MSCs' considerable therapeutic potential with respect to neurological ailments, sans the above limitations (Goodarzi et al, 2015).
Multiple risk factor groups have been established: First, risk factors linked to distinct stem cell classes' or types' innate cellular characteristics. Second, external risk factors emerging at the time of cell procurement, culturing, handling, and storage. Lastly, clinical risk factors (linked to surgical processes, immunosuppression, co-morbidities, and administration method and site. A key point to bear in mind is: two or more risk factors out of the aforementioned divergent categories may contribute to patient risk. Awareness of risk factors and likely risks with extant or other stem cell medicine can supposedly add to risk assessment of novel stem cell treatments (Herberts et al, 2011).
Results
Niche offers the ideal physio-chemical environment and regulatory molecules for cells to react in a specific way. The cells are utilized for therapeutic goals through separating them from the niche that can bring about undesirable results e.g. tumorigenicity, which is a big issue. Only a handful of researchers have noted that stem cell transplants could have negative side effects. The percentage of nestin positive cells found to have increased from day 47 to day 103 suggesting the formation of a tumor in the transplanted cells. An eighteen-year-old individual with injury to the spinal cord had olfactory mucosal cells transplanted to help him. The transplanting resulted in severe back pain and imaging revealed that there was a formation of a mass in the spinal cord (Bali et al, 2018). Studies have been done with a particular focus on PD and therapies have been formulated including those that take into account ADSC targets for long-term improvement. Choi et al. (2015) confirmed that intravenous hADSCs improved behavioral and motor performance.
Discussion
It has been proven that NSCs have a lot of potential since they provide neuro-trophic support and, therefore, directly reduce PD symptoms. Of all the currently used stem cell methods for fighting Parkinson’s disease NSCs have been proven to have the highest effectiveness in bringing stability to neurotrophin levels especially in mice. Nevertheless, NSC studies show transplantation is not always consistent or a success. Therefore, there is a need for more research before clinical application. Transplantation can be hindered by cellular mortalities or harvesting. And even though they are largely expected to work, more studies are needed to check their effectiveness and the safest method of administration (Hwang et al, 2018).
Stem cells research has shown by use of scientific data that stem cell transplants provide therapeutic benefits when used in the treatment of certain neuro degenerative diseases. The stem cells deliver therapeutic effects in a variety of ways but the actual intrinsic pathways are not known. Some of the pathways include paracrine effects, immune-modulation, differentiation, and proliferation. Pre-clinical body of research on stem cells shows that the benefits and drawbacks are dependent on stem cell source and type (Bali et al, 2017).
Conclusion
On the whole, stem cell treatment has created great hope among patients diagnosed with multiple degenerative problems and ailments; however, an in-depth assessment of likely risks and risk factors of stem cell-grounded medications is pivotal prior to its widespread approval for clinical administration. For every such medication, the likely patient risks must be appropriately assessed; moreover, distinct inherent stem cell characteristics as well as safety information already acquired about similar product kinds must be taken into consideration. Furthermore, external risk factors such as production, storage, handling, and therapeutic/clinical risk factors may generally contribute to patient risk. In the course of risk assessment, safety-related knowledge of similar medications based on stem cells might prove highly valuable. Established or recorded risks, established risk factors, and likely or anticipated risks ought to be taken into consideration as well during risk assessment (Herberts et al, 2011).
Further studies are needed to establish the best PD and AD model for treatment of the diseases. There is also a need to establish the best route of administration, doses, stages, and sources of stem cell transplants so as to find that which offers the most optimal therapeutic outcome for patients.
References
Alzheimer’s Association. (2015). 2015 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 11(3), 332-384. doi:10.1016/j.jalz.2015.02.003.
Bali, P., Lahiri, D., Banik, A., Nehru, B., & Anand, A. (2017). Potential for Stem Cells Therapy in Alzheimer’s Disease: Do Neurotrophic Factors Play Critical Role? Current Alzheimer Research, 14(2), 208-220. doi:10.2174/1567205013666160314145347
Goodarzi, P., Aghayan, H. R., Larijani, B., Soleimani, M., Dehpour, A. R., Sahebjam, M., … Arjmand, B. (2015). Stem cell-based approach for the treatment of Parkinson's disease. Medical journal of the Islamic Republic of Iran, 29, 168.
Herberts, C. A., Kwa, M. S., & Hermsen, H. P. (2011). Risk factors in the development of stem cell therapy. Journal of Translational Medicine, 9(1). doi:10.1186/1479-5876-9-29
Hwang, S., Gill, S., Pathak, S., & Subramanian, S. (2018, March 30). A Comparison of Stem Cell Therapies for Parkinson Disease | Published in Georgetown Medical Review. Retrieved June 11, 2019, from https://gmr.scholasticahq.com/article/3420-a-comparison-of-stem-cell-therapies-for-parkinson-disease
Railton, D. (2019, February 18). Stem cells: Therapy, controversy, and research. Retrieved June 11, 2019, from https://www.medicalnewstoday.com/articles/200904.php
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