The Stem Cell Technique in Treatment of Alzheimer's and Parkinson's Diseases - Essay Example

THE STEM CELL TECHNIQUE IS BEST FOR FUTURE TREATMENT OF BOTH ALZHEIMER’S AND PARKINSON’S DISEASES INTRODUCTION Among future treatment options for Alzheimer’s and Parkinson’s diseases are: stem cell procedure, gene therapy and deep brain stimulation. There is increasing knowledge emerging from stem cell research, regarding the development of an organism from a single cell, and the replacement of a damaged cell by a healthy cell in an adult organism. Stem cell therapies consist of treatment measures related to regenerative medicine. They have the potential to provide a renewable source of replacement cells “to treat various diseases, conditions and disabilities” (Slesnick, 2004, p.15) including Parkinson’s disease and Alzheimer’s disease. Thesis Statement: The purpose of this paper is to justify stem cell therapy as the best future treatment approach for Alzheimer’s and Parkinson’s disease, as compared to other options such as cell therapy and deep brain stimulation. DISCUSSION Currently available pharmacological therapies for Parkinson’s disease such as Levodopa, Selegiline, Amantidine, Anticholinergics, Dopamine receptor agonists, and Catechyl-O-methyl transferase (COMT) inhibitors can neither arrest nor reverse the progression of the disease; hence no cure has been found for PD so far. However, the symptoms can be managed with several different drugs which raise the levels of dopamine in the brain, or imitate the effects of dopamine (DA). Newly researched neuro-protective agents are Nicotine, Anti-inflammatory agents, Melatonin, Mono-amine oxidase-B (MAO-B) inhibitors, Selenium, Iron-chelators, Vitamins A, C, and E and other agents. They provide great possibilities for the development of future treatments; however the main challenge they offer is the necessity to modify them into versions that are more selective and potent. Additionally, “the development of drug delivery systems that can effectively deliver these molecules through site-specific mechanisms is vital to optimize their use” (Singh et al, 2007, p.40). The non-pharmacological treatments under investigation include PD vaccine, cell transplantation, gene therapy and surgical methods. PD vaccine is considered to be potentially effective for those who may inherit the disease due to familial PD. The future possibilities for a complete cure with the use of pleuripotent stem cells are immense. However, for cell transplantation to be carried out effectively, more viable and ethically sound sources are required. The practical applicability of gene therapy and surgical methods such as deep brain stimulation are reduced due to the side-effects that develop from these interventions (Singh et al, 2007). DEEP BRAIN STIMULATION IN THE TREATMENT OF PARKINSON’S DISEASE Ablative surgery for patients with Parkinson’s and other movement disorders, creates a permanent lesioning of tissue to ostensibly inhibit overactive neuronal activity. Deep Brain Stimulation (DBS) has replaced ablation of tissue in the basal ganglia and the thalamus. DBS mimicks ablation, without causing permanent damage (Benabid, 2003). Hardesty and Sackeim (2006) believe that the therapeutic properties of high frequency DBS on both white and grey matter targets are due to an excitatory axonal response. The mechanism of DBS is based on a combination of inhibition and excitation, resulting in neuronal jamming and silencing, as well as axon stimulation. By switching off the disrupting activity causing the movement disorder, the application of a new type of frequency that has beneficial effect, is possible. This is particularly relevant in Parkinson’s disease “where there are abnormal synchronization and irregular discharges in the subthalamic nucleus that must be turned off to achieve a therapeutic effect” (Garcia et al, 2005, p.209). New research has introduced neurosurgical approaches based on ready to use and commercially available equipment for deep brain stimulation of the subthalamic nucleus, and also lesion or stimulation of the globus pallidus to a lesser extent (Starr et al, 1998). According to Albert et al (2009), Deep Brain Stimulation is conducted with the help of chronically implanted electrodes in the brain to stimulate neuronal networks electrically. The DBS equipment consists of an electrode(s) depending on unilateral or bilateral stimulation, which is approximately 1.25 mm in diameter with four contacts, a pulse generator or battery, and an extension connecting the electrode and the generator/ battery (Andrews, 2003). Deep brain stimulation procedures are now routinely undertaken on patients with advanced Parkinson’s disease. But, these procedures cannot be expanded to treat the entire population of patients with advanced PD, mainly because of their high cost and requirement for very skilled stereotactic neurosurgeons. Therefore, the search for alternative neurosurgical approaches continues through ongoing research and development (Bjorklund et al, 2003). Heo et al (2008) conducted a study using neuropsychological testing to determine cognitive and mood effects of bilateral Subthalamic Nucleus Deep Brain Stimulation (STN DBS) in patients with Parkinson’s disease (PD) at 6 months and 1 year post-operatively. The evidence reveals that the surgery results in motor improvement in the patient; however, there is a subtle decline in frontal lobe function and memory developed after STN DBS. Baseline attributes such as age at onset of Parkinson’s disease, a high level of education, and L-dopa Equivalent Dosage (LED) are risk factors which predict postoperative cognitive decline. There is no correlation between motor improvement and cognitive decline, which indicates that the deep brain stimulation was spatially specific within the subthalamic nucleus (STN). Peron et al (2010) conducted a research study using STN DBS therapy on 24 Parkinson’s disease patients, another group of 20 PD patients treated with apomorhine, assessing the groups 3 months before and after treatment. The two patient groups were compared with a group of thirty healthy matched controls. The main aim was to confirm that STN DBS led to impairment of the recognition of facial emotions (RFE). The researchers ruled out the effect of the natural progression of the disease with regard to effect of Deep Brain Stimulation, and also assessed the influence of modifications in dopamine replacement therapy (DRT) after the STN DBS intervention. The results demonstrated that RFE for negative emotions such as fear and sadness “was impaired in only the STN DBS group in the posttreatment condition, and was unrelated to DRT” (Peron et al, 2010, p.1). Results confirm the selective decline in recognition of facial emotions, caused by STN DBS; further, it did not arise from the disease’s natural progression or from modification in dopamine replacement therapy. Patients with Parkinson’s disease (PD) who undergo pallidal surgery or subthalamic nucleus stimulation reveal a decline in verbal fluency. This decline in verbal fluency is the most consistent neuropsychological sequela of deep brain stimulation (DBS) for Parkinson’s disease. The clustering and switching components of semantic or category fluency: the oral naming of items available in supermarkets, were examined at baseline and four months after intervention with deep brain stimulation or pallidotomy. Post-operative declines were observed for supermarket fluency total score and switching, but there was no decline for average cluster size. This evidence supports the proposed hypothesis that decline in semantic fluency after pallidal surgery reveal a disruption of frontal-basal ganglia circuits mediating “the efficient shifting between semantic categories, or perhaps efficient access to categories, rather than a degradation of semantic stores” (Troster et al, 2002, p.207). According to De Gaspari et al (2008), the decline tended to be worse in patients with baseline poorer cognitive status and lower condition of depressed mood. Impairment of shifting suggests prefrontal dysfunction, possibly due to disruption of fronto-striatal circuits along the surgical trajectory and/ or caused by the high frequency stimulation itself. GENE THERAPY FOR TREATMENT OF ALZHEIMER’S AND PARKINSON’S Evidence from research has established that Nerve Growth Factor (NGF) prevents neuronal death or age-related atrophy in the adult brain. In Alzheimer’s disease (AD), cholinergic neurons in the basal forebrain die due to atrophy. This process is considered to form the basis for attention deficit and overall cognitive decline in AD. Thus, the delivery of nerve growth factor into the brains of patients with Alzheimer’s disease may reduce or prevent the cholinergic component of cell loss. However, the transmitting NGF into the brain is difficult, since the active, beta component of the molecule is large and polar, and cannot cross the blood-brain barrier. With the help of intracerebroventricular infusions or intermittent injections, NGF was successfully delivered into the CSF of rodents. Based on research findings, “the best method of delivering NGF to patients with Alzheimer’s disease was thought to be intra-cerebroventricular infusion” (Tuszynski, 2002, p.52). However, the infusions were unsuccessful in delivering NGF to patients with Alzheimer’s disease, due to adverse outcomes including weight loss and pain (Jonhagen et al, 1998). Appropriately controlled clinical trials conducted carefully and obectively are required, to determine the ultimate usefulness of growth-factor gene delivery for neurological diseases. Additionally, improvements need to be made in the design and safety of gene-therapy vectors, to contribute to the advancement of gene therapy-based techniques. One of the limitations of this approach is that the amount of gene product delivered cannot be controlled. To improve the safety aspect of gene therapy, it is important to develop vector systems in which the expression of a gene can be regulated, and turned off if necessary. A promising new vector system with a tetracycline-sensitive element incorporated into its structure can be used to eliminate the biological effects of ex vivo NGF gene therapy in animals (Tuszynski, 2002). The extent and duration of therapeutic gene expression is another issue that impacts the potential efficacy of gene therapy. Earlier, many of the therapeutic genes used in these studies were expressed for a few weeks or less, thus limiting their efficacy. However, more recent vectors are capable of maintaining gene expression in vivo for months, and even years. “These improvements are a result of the use of novel promoters, expression enhancers, and post-transcriptional stabilisers of mRNA” (Tuszynski, 2002, p.56). Additionally, modern vectors induce only a negligible inflammatory response. Thus, sustainable gene expression is possible with the new generation of adeno-associated virus, lentivirus, and “gutless” adenovirus vectors. STEM CELLS Stem cells are unique in that they are “unspecialized cells that can reproduce themselves for long periods of time by cell division” (Slesnick, 2004, p.15). Further, under special physiologic and experimental conditions they can be converted into specialized cells with specifically dedicated functions, such as secretory neurons in the brain or beating cells in the heart. The two major types of stem cells in the body include embryonic stem cell and the adult, somatic stem cell. Embryonic stem cells lie within the cell mass of the blastocyst which contains a disc of about thirty cells, with the blastocyst developing about two to five days after fertilization. Surrounding the blastocyst is a mass of cells forming the trophoblast, and the hollow cavity inside the embryo is the blastocoel. Each of the thirty embryonic stem cells is pluripotent and is capable of transforming into any cell of the body. The adult somatic stem cells migrate with the tissue they form. The three common properties of all stem cells irrespective of their origin include: capability for self-renewal by dividing for long periods of time as a stem directs, ability to remain indefinitely unspecialized, and the capacity for producing specialized cell types. Evidence from recent research reveals that due to their plasticity blood stem cells can develop into a number of different cells “such as nerve cells and liver cells” (Slesnick, 2004, p.15). FUTURE TREATMENT OF PARKINSON’S DISEASE USING STEM CELLS The commonly occurring neurodegenerative disorder Parkinson’s disease is caused by a loss of dopamine producing neurons, causing tremors, rigidity and an abnormal decrease in mobility. Parkinson’s disease is considered to be the first condition to which treatment with stem cell transplantation can be applied. The factors supporting this concept include knowledge about the cell type DA: dopamine producing neurons needed to relieve the symptoms of the disease (Slesnick, 2004). Twenty years ago, research based on clinical trials using dopamine neuron replacement therapy for Parkinson’s disease (PD) were first undertaken in Sweden, by transplanting aborted fetal brain tissue into the brains of patients with PD (Lindvall et al, 1990). Researchers in the field have successfully developed techniques to induce embryonic stem cells to differentiate into cells with several of the functions of DA neurons. It is expected that in the future, “the successful creation of an unlimited supply of dopamine neurons could make neurotransplantation widely available for Parkinson’s patients” (Slesnick, 2004, p.16). This is supported by Brundin and Bjorklund (2009), who found from research on rodent and primate models of Parkinson’s disease that transplanted dopamine neurons extracted from embryos and fetuses restore dopaminergic neurotransmission in the area of the striatum reached by outgrowing axons. The spontaneously active grafted neurons release dopamine at both synaptic and nonsynaptic sites, thus reversing or relieving partially the Parkinson-like motor impairments caused by damage to the nigrostriatal system. Clinical trials undertaken on patients with Parkinson’s disease have proved that immature dopamine neuroblasts survive and function in the brains of patients with Parkinson’s disease. Further, they restore striatal dopamine release, and are therapeutically beneficial. However, the clinical grafting protocols employed at present need to be improved to ensure reproducibility of successful outcome and symptomatic relief, as well as the prevention of unrequired movements that some patients manifest as a side effect. “Dopamine neurons derived from stem cells may provide an inexhaustible source of donor tissue that can be used in future clinical trials” (Brundin & Bjorklund, 2009, p.649). On the other hand, some hurdles that need to be overcome to reap the benefits of stem cell therapy for Parkinson’s disease, include the following: To increase the safety of stem cell therapy, and to eliminate the possibility of dyskinesias or abnormal movements which occur in transplant patients, by identifying the underlying mechanisms. The problem of dyskinesias can be tackled with the help of stem cells “if more defined dopamine populations can be produced, or engineered by using inducible promoters to control dopamine release” (Svendsen, 2008, p.412). For increased control of neuronal activity, a drug to activate dopamine production may need to be administered to the patient. The next hurdle is more difficult to overcome. The stem cells are deposited ectopically in the striatum, a forebrain structure, by most of the current transplant techniques. This location is convenient for dopamine neurons to connect with their target; however, the endogenous, damaged dopamine neurons are situated deep in the midbrain, several centimeters away. To restore the original circuit, dopamine neurons must be engrafted back into the midbrain, and then subjected to long-distance axon regeneration to targets in the striatum. This technique has the potential to restore physiologically relevant input to the new dopamine neurons, and may even provide the normal fine control over dopamine release unique to this system. However, some studies revealed that extensive long-distance axonal outgrowth into the adult brain is difficult to achieve (Svendsen, 2008). The last hurdle confronting dopamime neuron replacement strategies is that Parkinson’s disease pathology is not limited to the loss of dopamine neurons. In PD patients, many other systems deteriorate, and may need to be examined and treated, along with restoring dopamine signals in the brain. However, dopamine replacement may only be one aspect of the treatment required. “Stem cells also produce astrocytes, which are able to modulate synaptic transmission, toxic glutamate levels, and the blood-brain barrier function” (Svendsen, 2008, p.413). Further, they can be genetically modified to release powerful drugs within particular brain regions. Thus, stem cells provide opportunities for new potential avenues of therapy for PD patients, complementing current treatments, while recovery to normalcy from dopamine neuron transplantation may be possible only as a future prospect. According to Bjorklund et al (2003, p.442) “the first step in the development of a stem-cell based therapy for PD is to find a renewable source of midbrain dopaminergic neurons”. Such a source would eliminate several of the ethical and practical concerns related to using human fetal tissue. It would also provide a time frame for cell characterization, purification, and banking before transplantation. At least four types of stem cells have been studied for this purpose. They include neural stem cells, non-neural adult or fetal stem cells such as bone marrow or skin cells, human embryonic stem cells, and nuclear transfer or parthogenic stem cells. These alternative cell types may offer substitutive cell therapy for all patients with advanced Parkinson’s disease. Besides stem cell therapy, other treatment options for Parkinson’s disease include ablative surgery and deep brain stimulation (DPS), which attempt to compensate for the biochemical defect in Parkinson’s disease. This is different from the regenerative stem cell therapy and cell therapy which are based on correcting the shortcoming through transplantation. The restorative therapies, intracerebral cell transplantation and growth factor infusion, attempt to correct the biochemical defect of Parkinson’s disease “by replacing lost dopaminergic cells or promoting the survival of host dopaminergic cells. However, the restorative therapies are completely experimental and limited to a few research centres (Starr et al, 1998). Further, transplantation of embryonic stem cells, or the human fetal neural tissue is a deeply ethical issue (Bjorklund et al, 2003) since it is not readily available when required, and concerns a potential human life that is terminated. Even when stem cells are extracted from embryos or fetuses which are scheduled for abortion for any reasons, the ethical aspect is considered to be of a serious nature. STEM CELL THERAPY FOR ALZHEIMER’S DISEASE Although major advances have been made in understanding the pathology of Alzheimer’s disease (AD), and in developing new treatments, Holtzman (2008) states that there has been no evidence of therapeutic improvements. Therapeutic effectiveness is higher when patients are treated in presymptomatic or early clinical stages, prior to neuronal degeneration. Shaw et al (2007) note that early diagnostic methods are being developed; and new symptomatic and disease-modifying treatments are being established (Wisniewski, 2009; Weksler et al, 2009; Biran et al, 2009). Generally, most AD patients who seek treatment already have neuritic plaques, neurofibrillary tangles, and neurodegeneration. At this advanced stage of the disease, a multi-dimensional approach to halt Ab toxicity would be more beneficial to promote cell survival and/ or replace lost cells. Blurton-Jones et al (2009) and Nagahara et al (2009) report that increasing brain-derived neurotrophic factor (BDNF) levels is unlikely to reverse Alzheimer’s disease pathology. Shihabuddin & Aubert (2010, p.850) reiterate that “for short-term treatments, BDNF-based therapies could be beneficial to rescue neurons and cognitive functions”. For longer treatments during the course of the diseasewith its growing pathology, both BDNF and anti-Alzheimer therapies would need to be integrated appropriately for optimal effectiveness. THE FUTURE POSSIBILITIES FOR STEM CELL THERAPIES IN AD AND PD Cell replacement for functional brain repair is a complex area. Each neurodegenerative disease may require a case-specific approach to effectively rescue or replace particular types of neurons and neuronal networks. For example, stem cells may be required to differentiate into supporting cells, or may be genetically modified to release sufficient and appropriate trophic factors for the degenerating cells. On the other hand, stem cells may be directed to differentiate into neurons of a particular phenotype to release the neurotransmitter needed for a given neurodegenerative disorder. Thus, stem cell therapy could aim to promote “cholinergic and dopaminergic cell survival and neurotransmission for AD and PD respectively” (Shihabuddin & Aubert, 2010, p.850). In animal models of PD and AD, research is underway for replenising a specific neurotransmitter, trophic factor, or cell type, and rescuing behavioural deficits in the models. Promising outcomes from these studies may lead to future clinical trials. Gradually, with increasing knowledge about these disorders, it may become optimal to rescue several neuronal systems, perhaps at different stages of the disease. Thus, it is now established that AD and PD, classically and respectively categorized as cholinergic/ dementia and dopaminergic/ motor disorders, overlap markedly in clinical symptoms, and in their deficits in neurotrophic factors and neurotransmitter systems (Zaccato & Cattaneo, 2009). Stem cell therapy provides the advantage of being conducive to genetic engineering that can be used to control the timely release of trophic factors and neurotransmitters. Currently, the delivery of stem cells across the blood-brain barrier involves invasive surgeries with their associated risks. Non-invasive techniques for delivering therapeutic molecules, genes and cells are under intensive investigation. Intranasal delivery of therapeutic molecules is being explored, especially for the delivery of trophic factors for Alzheimer’s disease. Other techniques include focused ultrasound in the presence of microbubbles and guided by magnetic resonance imaging to reversibly and locally increase the permeability of the blood-brain barrier, as well as biomaterials which assist therapeutics to cross the blood-brain barrrier. This helps to deliver stem cells in a safe and less invasive manner than intracranial transplantation currently being carried out (Hynenen, 2008). Similarly, developing non-invasive methods to stimulate endogenous stem cells in the brain is also a promising field in the prevention and treatment of disease, states Van Praag (2009). Another challenge to overcome in the use of stem cells for transplantation in neurodegenerative disorders is the possibility that the pathology of the disease itself spreads to the transplanted cells (Kordower & Brundin, 2009). This is a particular concern for Human induced Pluripotent Stem Cells (hiPSCs) drawn from the patient’s own skin. “While autologous hiPSCs present several advantages, including lower risk of immune rejection, it is possible that these cells will have an increased susceptibility to develop PD pathology” (Shihabuddin & Aubert, 2010, p.851). Over time, the pathology may cause degeneration of initially healthy transplanted cells, which would lead to their becoming ineffective in action. Stem cell therapy is in the initial stages of development, for treating Alzheimer’s disease and Parkinson’s disease. It is crucial that preclinical and clinical research continues to explore the potential of cell and gene replacement therapies, since the neurodegenerative disorders have no treatments available to cure the diseases. It is believed that knowledge based on advances in research and development related to stem cell biology, gene therapy, and neurodegeneration should be combined together, to formulate optimally efficient treatment for AD and PD. CONCLUSION This paper has highlighted treatment options for Alzheimer’s and Parkinson’s disease. As compared to other alternatives such as gene therapy and deep brain stimulation, the evidence from research indicates that stem cell therapy is the best future treatment approach for these conditions. Deep brain stimulation in the treatment of Parkinson’s disease, gene therapy for Alzheimer’s disease (AD) and Parkinson’s disease (PD), the future treatment of Parkinson’s disease using stem cells, stem cell therapy for Alzheimer’s disease, and the future possibilities for stem cell therapies in AD and PD have been investigated. Deep brain stimulation cannot be routinely undertaken with large sections of the population because of the high costs involved in the procedure, and the requirement for very skilled stereotactic neurosurgeons. Further, subthalamic nucleus deep brain stimulation (SN DBS) causes a selective decline in the recognition of facial emotions, as well as deterioration of verbal fluency. Similarly, the duration of gene expression is another aspect that influences the potential effectiveness of gene therapy. Rather than cell replacement and regrowth of damaged circuitry, using stem cells as cellular vectors to prevent or provide relief for neurological disorders is considered to be the more viable alternative. Shiabuddin and Aubert (2010) support this perspective, and state that in AD and PD, an integrated use of gene and stem cell therapy may be the optimal option. Because of the complicated neural circuitry of the brains which will not allow the reversing of pathology at advanced stages of the diseases, the more advanced conditions of Alzheimer’s disease and Parkinson’s disease cannot be treated by stem cell therapy. Thus, neuronal loss and scarring are likely to remain as irreversible processes at least for the near future. Contrastingly, when the disability is due to continued inflammation, cellular dysfunction due to lysosomal storage, or a reduction of trophic factors or neurotransmitter release in PD and AD, normal function of the brain can be restored. Therefore, it is vital that therapy is initiated early, to achieve successful outcomes in stem cell therapy. Shihabuddin & Aubert (2009) add that it is also essential to develop tools to diagnose AD and PD in their earliest presymptomatic stages. Future research in the area of stem cells should determine whether reversal of lesions can actually arrest the degeneration in mental development. 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