Cell Replacement Therapy for Human Neurodegenerative Disorder - Literature review Example

A review on Cell Replacement therapy for Human Neurodegenerative Disorder – Parkinson Disease and Alzheimer’s Disease Name Course Name and Code Date Introduction Neurodegenerative disorders or diseases are associated and characterized by neurodegenerative changes or by the chronic and progressive deterioration of the individual’s neural functions, which culminates into loss of memory, impairment in cognitive abilities, as well as impairment in the motor coordination. The continued loss of the mentioned abilities may finally result into permanent paralysis together with lose of sensation. A wide range of these neurological disorders is hereditary including Parkinson’s disease (PD) Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Spinal Muscular Atrophy (SMA). Generally, Alzheimer’s disease is regarded as the most common form of dementia. According to Ferri and others, estimated that more 24.3 million people globally were suffering from dementia in 2005 and the number of patients suffering from this neurological disease will increase to more 81.1 million by 2040. Lunn et al., on the other hand established that approximately 7 million patients in the US are affected by various neurodegenerative diseases. Accordingly, it has been noted that as life expectancy increases, so is the increase of patients suffering from these disorders, which on the other hand results into a heavy socio-economic burden to the affected individuals together with their families throughout their entire lives. Currently, no effective cure has been discovered for these neurodegenerative diseases. Accordingly, there are few cellular models that summarize disease pathogenesis together with assistance in drug screening. However, cell replacement therapies using stem cells has been found to be a potential approach in treating these diseases based on the fact that they are characterized by progressive neuronal loss. After Takahashi and Yamanaka documented and reported their findings in programming human and mouse fibroblasts into pleura-potent cells, there has been a remarkable advancement in pleura-potent stem cells. This paper is a review on Cell Replacement therapy for human neurodegenerative disorder – Parkinson disease and Alzheimer’s disease. For this reason, the paper discusses the disease modelling, stem cell therapy and neurodegenerative diseases particularly Parkinson’s disease and Alzheimer’s disease. Figure 1: Showing an overview of the use of iPSCs Adapted from (Wu, YP et al, 2010) Disease Modelling According to Young (2009), various studies that have been conducted with an aim of elucidating the pathogenesis of neurodegenerative diseases in human beings base their studies on post-mortem tissues and transgenic animal models. Contrastingly, post-mortem tissues are rarely available and in most cases represent the final phases of the disease. Philips et al., (2009), established that murine models largely contribute to the greater understanding of human neurodegeneration; however, they do not entirely recapitulate the neural phenotype of human beings. Cellular models are constructed by first generating the induced pluripotent stem cells (iPSCs) lines from patients. Park et al. (2008) derived disease specific iPSCs from patients suffering from various genetic diseases. This was a fundamental step into the establishment of neurodegenerative disease modelling. With regard to this development, various cell lines from patients with dissimilar neurodegenerative disorders have been generated. For instance, some of the disorders show the in vitro phenotypes while others still demand for an in-depth investigation to validate their phenotypes. SMA is a neurodegenerative disorder that is well characterized in iPSCs-based in vitro disease model. Despite the commendable strides made in neurodegenerative disease modelling, there are still issues involved in using iPSCs. For instance, the variations in pluripotent stem cells. The hESCs derived from human blastocysts seem normal, however they showed massive differences in their differential potential (Osafune et al., 2008). Accordingly, the iPSCs derived from same donor fibroblasts displayed variable neuronal differential potential (HU BY et al., 2010). Regardless of these variations, the use of chemical inhibitors of TGFβ and BMP signaling substantially reduces the neuronal differentiation variation despite of their cellular sources (Kim DS et al, 2010, and Chambers et al, 2009). Similarly, the large scale characterization of six hESC lines together with 16iPSC lines from patients suffering from ALS indicate standard neuronal differentiation condition when using retinoic acid, BDNF, GDNF, and CNTF which reveal quantitative difference in motor neuron differentiation with regard to different cell lines. On the other hand, the use of TGFβ and BMP inhibitors significantly help in reducing the differences. Following this observation, it is recommended to improve the in vitro differentiation condition in order to recapitulate the phenotypes of the neurodegenerative disease under investigation while at the same time minimizing cellular bias. The late onset and the polygenic traits are unique occurrences and hence must and should be considered in neurodegenerative disease modelling in vitro. Bertram and Tanzi (2005) estimate that diseases with early onset with the familial cases only account for less than 10% of each neurodegenerative disease. This delayed onset is extremely difficult to recapitulate in vitro. For this reason, there is need to mimic the physiological aging in vitro in order to accelerate the manifestation of the phenotype and hence to succeed in modelling. Another alternative is by employing the use of iPSCs derived from patients with proper definition of familial genetic mutation. Similarly, having relatively early onset always elucidates the common pathogenesis of the shared disease with the late onset ones, for example the early onset of presenilin 1 and presenilin 2, which is a mutant of Alzheimer’s patients. Disease screening Drug development for neurodegenerative diseases is an extremely expensive task, Kola and Landis (2004) estimate that the cost for neurodegenerative diseases drug development was approximately $900 million. The failures in this activity occurred during the final phases of the development particularly IIb and III clinical trials. Similarly, approximately 90% of drugs in human clinical trials are not approved for marketing thus, they do not meet the treatment threshold required. The massive rates of failures in these clinical trial is strongly linked to the lack of efficacy together with clinical safety in patients mainly because of the current limits in disease models in recapitulating the human disease and in testing drug safety. Given these facts, disease specific iPSCs provides an excellent and unique chance for drug discovery. For instance, the materials of screening iPSCs are human cells, which have been affected by the disease, but they are not unrelated immortalized cell lines artificially tailored to mimic the disorder. Additionally, target of screening, iPSCs can be distinguished into specific neuronal subtypes relevant to the disorder phenotypes, like Parkinson’s disease dopaminergic neurons and/or motor neurons in ALS. Given this understanding, the molecules screened as effective for the target cells are potentially expected to give same efficacy when treated to the patient. Testing the toxicity of neurodegenerative diseases drugs is done by directly using the iPSCs derivatives. Screening of these drugs for their efficacy, the neurotoxicity is simultaneously tested during the process. Furthermore, cell types including cardiomyocytes as well as hepatocytes are significantly vital in determining the cytotoxicity of the chemicals differentiated from the iPSCs (Lausteriat et al, 2010, and Braam et al, 2009). The proper and best screening is by using iPSCs for highly efficient chemical and low toxicity; this is essential in decreasing the massive costs of drug development in human clinical trials. Disease treatment Cell therapy is mainly the replacement or introduction of functional cells to restore the destroyed or damaged neural tissues in neurodegenerative diseases. With regard to the extensive and intensive research into neurodegenerative diseases, researchers have developed cell transplantation therapies which have significantly resulted into the use of neuronal stem cells (NSCs), mesenchymal stem cells (MSCs) and hESC-neuronal cells (Karussis et al, 2010, and Corti et al 2008). The NSCs and MSCs are easily differentiated into neural lineages. Contrastingly, these cells display limited potential of self-renewal of neural progenitor cells (NPCs) which can further be distinguished into various functional neuron and glia (Zhang et al, 2001). Accordingly, the advances in the differentiation process of neuronal development have resulted into successful specific neurons generation from hESCs. It has also been established that human iPSCs have close resemblance to hESCs and hence hESCs can successfully be applied to iPSCs. Parkinson’s disease can effectively be treated using iPSCs cell therapy. The main characteristic of the PD is that it results from the loss of selective dopaminergic neurons in the substentia nigra. For this reason, the replacement of the destroyed dopaminergic neurons will automatically alleviate Parkinson’s disease symptoms. Other key features of the PD are; the patients will experience progressive motor dysfunction including tumours, gait disturbances as well as rigidity. It is also recommended that prior to using iPSCs in human treatment, the safety of the cells for clinical applications should exhaustively conducted (Parish and Arenas, 2007). For instance, the retro and/or lentiviral transduction systems should be used to iPSCs generation. Important to note, the viral systems used can result into rapid chromosomal integration thus culminating into unknown and unpredictable genetic dysfunction. The insertional mutagenesis caused by the retroviral vector can be avoided through different established approaches for generating iPSCs like plasmid transfection, non-integrating episomal vector transfection, and piggybag transposon (Kaji et al, 2009, and Woltjen et al, 2009). In the same line of discussion, Kim et al, (2010) generated hiPSCs successfully through direct delivery of known and defined reprogramming proteins into fibroblasts. The hiPSCs were then differentiated into functional dopaminergic neurons. Accordingly, the NPCs that were derived from protein-based iPSCs displayed similar characteristics when they were compared to those derived from hESCs. These studies also found out that dopaminergic neurons extracted from iPSCs displayed gene expression and electrophysiologic property that was identical to the midbrain dopaminergic neurons. Equally important, the neuronal cells exhibited the ability to restore the motor deficit when they were translated into PD rat models thus displaying the functional significance of the in vitro differentiated cells (Newman et al., 2009). It has also been established that the protein-based reprogramming approach should and must rise above the extremely low reprogramming efficiency. Similarly, for clinical safety purposes, selection of the preferred and terminally differentiated cells is strongly recommended. Stem Cell and Neurodegenerative Diseases This section is dedicated towards reviewing the scientific basis of stem cell therapies and their prospects in Parkinson’s disease and Alzheimer’s disease (Brindley et al., 2011). For these neurodegenerative diseases, a description of the ways in which stem cells are used to treat the identified disorders, provide the prospects and problems of translating laboratory findings into clinically relevant therapies. Stem cells and Parkinson’s disease Figure 2: Showing an overview of Stem cell–based therapies for PD (Invest, 2010) This neurodegenerative disorder is associated with progressive loss of dopaminergic (DA) neurons particularly in the substantia nigra pars compacta (SNpc) together with the decrease in the dopamine. In the Parkinson’s disease, the continued loss of the DA neurons in the SNpc results into the impairment in information processing in the basal ganglia. The specific symptoms of Parkinson’s disease as already mentioned above include poor or impaired movement, rigidity, tremors, and postural instability. The therapeutic treatment of PD is mainly base on the oral administration of L-dopa and dopamine receptor agonists and on deep-brain stimulation in the sub-thalamic nucleus (Wu, YP et al, 2010). Despite the effectiveness of pharmacological treatment to some of the PD symptoms, it has various side effects and limitations due to the decrease in effectiveness over time as the symptoms progressively develop. Given this observation, there is an alternative approach, which has been found to be more effective in the restoration of the damaged or destroyed DA system; the transplantation of DA synthesizing cells (Wu, YP et al, 2010). The human stem cells can be effectively used as the source for Parkinson’s disease treatment. Different studies have established that stem cells over expressing neurotrophic factors are essential in providing neuro-protective as well as neuroregenerative effects when they are grafted in animal models. For instance, the recent continued divisions of immortalized cell lines of neural stem cell (NSCs) have been produced through the introduction of oncogenes. The immortalized NSCs lines have a positive effect particularly in the basic studies of neural development as well as cell replacement therapy (Wu, YP et al, 2010). In order to meet the clinical threshold, therapy based on stem cells must culminate into mobility improvement in the long-run. It must also ameliorate current intractable symptoms, and/or counteract disease progression. Clinical transplantation of human fetal DA neurons exhibits that cell replacement can significantly result into major, long-lasting restoration in some patients. In order to operationalise stem cell therapy for Parkinson’s disease, dopaminergic neurons that have features similar to substantia nigra must be produced in large numbers (Wu, YP et al, 2010). Accordingly, the DA neurons degenerated from hESCs and NSCs, their survival in animal models was found to be poor and thus there is need to increase their count before clinical application (Hwang and Ong, 2009). It is extremely important to save the existing neurons from dying through transplanting human stem cells engineered in order to express neuroprotective molecules such as galial-cell-lines-derived neurotrophic factor (GDNF). In accordance with this, another study which has displayed that retinoic acid treatment together with transplanting ESCs to the lessioned brain has the potential of generating putative DA neurons as well as functional recovery in Parkinsonian rat models (Wu, YP et al, 2010). Similarly, this study established that L1 – overexpressing stem cell-derived neurals aggregates could significantly improve survival and migration of transplanted cells, differentiation into DA in the 1 – methyl – 4 – phenyl – 1, 2, 3, and 6 – tetrahydropyridine mouse model of PD (Wu, YP et al, 2010). Consequently, the growth factor effects on embryonic DA neuron grafts were recently investigated. The data derived from this study suggest that long term and continuous neurotrophic factors support from the Zuckerkandl’s organ to the transplanted NSC derived DA neurons, significantly enhanced their survival, axonal arborization together with the integration with the host cells, thus culminating into long-term functional restoration in the PD model in rats (Wu, YP et al, 2010). Given these facts, it is medically and scientifically significant to analyze major refinements of cell therapies with regard to Parkinson’s disease. Stem cells and Alzheimer’s disease Figure 3: Showing an overview of stem cell – based therapy (Invest, 2010) The major characteristics of Alzheimer’s disease are continued neuronal and synaptic loss in the brain, which involves the basal forebrain cholinergic system, amygdale, hippocampus as well as various cortical regions of the brain (Prather et al. 2009). Despite the fact that Alzheimer’s disease is associated with massive neuronal loss, it only occurs in very few specific brain structures including the hippocampal CA1 and CA 2 areas, the entorthinal cortex as well as the locus coeruleus, extended regions of the brain are mainly affected by pathological adjustments together with the decreased neuronal metabolism (Wu, YP et al, 2010). The available therapies today including acetylcholinesterase inhibitor treatment are mainly used in improving cholinergic function but only give partial and temporary alleviation of AD symptoms. Similarly, the pathological variations in AD offer a challenging environment for cell replacement. The available information shows that neural stem cells discharges diffusible factors that are helpful in enhancing the survival of the old and degenerating neurons in human brain (Wu, YP et al, 2010). Amyloid precursor protein of AD has been associated with various neurobiologic processes, however, there is no direct evidence supporting this claim (Wu, YP et al, 2010). Investigations into this disorder are confounded by the presence of two partially redundant homologues, APLP1 and APLP2 (Nugent et al. 2009). Stem cell culture provides an outstanding tool to evade the issue of absence of APP/APLP triple knockout mice and thus is essential in exploring the usability of amyloid precursor protein in vitro as well as in vivo (Wu, YP et al, 2010). The abnormality caused by morphology of neutrally – differentiated NSCs have been identified and are also seen in NSCs, which is transferred with wild – type APP. It has been found out that the rate of neuroregeneration in adult is minimal and it may remain like that in the end, and this deficiency significantly decreases the normal brain function (Wu, YP et al, 2010). Furthermore, using transplantation therapy for Alzheimer’s disease with NSCs is unlikely to be effective and essential in situations where APP metabolism is distorted and thus might result into increased gliogenesis (Wu, YP et al, 2010). APP processing regulation is always considered when developing effective NSCs transplantation therapy for AD patients (Mason et al., 2011). Given the fact that stem cells can be genetically modified in order to carry new genes as well as have high abilities particularly after brain transplantation, the can effectively be used instead of fibroblasts which have low mobility capacities following transplantation for delivery of nerve growth factor (NGF) for effective prevention of degeneration of basal forebrain cholinergic neurons (Wu, YP et al, 2010). On the other hand, due to the fact that stem cells can genetically be modified as well as have excellent migratory capacities after transplantation, they can be used for delivery of factors which can modify or improve the course of the AD (Nugent and Ng, 2009). This approach is anchored by the fact that forebrain grafts of fibroblasts produce NGF, which neutralize cholinergic neuronal death, while at the same time stimulates cell function together with enhancing memory in animal models, and above all have resulted into substantial benefits I patients suffering from Alzheimer’s disease (Wu, YP et al, 2010). General issues in developing stem cell-based therapies for neurodegenerative disorders Translating the current available knowledge of stem-cells into treatment or cure for neurodegenerative diseases; there are four main issues must extensively be considered. For instance, it is necessary and essential to define the requirements for the stem cell based approach for clinical competitiveness as well as the acceptable patient risks (Wu, YP et al, 2010). From the discussion above, it is evident that neurodegenerative diseases widely differ with regard to the level of disability caused together with the therapeutic treatment options available. For example, patients suffering from Parkinson’s disease are considered to have a normal life expectancy and most importantly, various drugs have been found to be effective during the initial stages of the disease (Wu, YP et al, 2010). Accordingly, in advanced stages of the disorder, there are valuable treatments for the symptoms. On the other hand, no effective cure has been found for the ALS, which is a rapidly progressing and fatal disorder (Wu, YP et al, 2010). Given these two distinct observations, it is important to consider these disparities when developing clinical application of an experimental and potentially risky stem cell based therapy. Secondly, the pathology of the disease must determined the type of cells to generated from stem cells; in cell replacement therapy, different neurodegenerative disorders require different types of cells. For example, alleviation of the PD and ALS require cells with DA and motor neurons properties respectively, on the other hand, cell replacement in Alzheimer’s diseases and stroke need different types of cells for its effectiveness to be achieved (Wu, YP et al, 2010). Experts in this field have also established that disease pathology have an effect on the cells derived from the transplanted, intrastriatal grafts of embryonic mesencephalic tissues exhibits more than a decade after implantation in the PD patients (Wu, YP et al, 2010). This is usually the case when patient-specific cells are generated through therapeutic cloning or by induced pluripotent stem cell technology, which results into extended susceptibility to the disease process. Consequently, before clinical application, the stem cell-based therapy must be demonstrated in animal models to establish the effectiveness of the therapy; substantial improvement in the functional deficits, which are similar to the deteriorating, conditions in patients (Wu, YP et al, 2010). Contrastingly, the behaviour of stem cells and/or in vitro differentiated cells after transplantation in animal models is limited to only reflecting how the cells will behave in patients. Accordingly, they may not mimic all aspects of the pathology of human conditions, which might lead to lack of efficacy of the stem cell-derived product in clinical trials. In the same line with the above, it is extremely important to determine the biological mechanism with regard to the underlying effects of stem cell based on therapies in animal model (Laustriat, Gide, and Peschanski 2010). For patients to achieve optimal recovery from neurodegenerative disorders, neuronal replacement as well as partial reconstruction of neuronal circuitry including the restoration of striatal DA transmission Parkinson’s disease should be considered as the sole objective. However, it is important to note that stem cells have the capacity of increasing functional improvements that are clinically valuable particularly through other mechanisms like immunomodulation (Wu, YP et al, 2010). Conclusion The recent studies in stem cell therapies have the potential of resulting into the development of radical new therapies for various neurodegenerative disorders, which lack effective treatment. The progressive and continuous development of different therapeutic approaches to generate different types of human-derived neurons as well as glial cells essential for replacement therapy based on the pathology in regard to specific disorders. Patient specific cell have been found to be useful and can now be produced from iPSCs. Accordingly, NSCs in adult brain have the capacity to generate new neurons as well as glial cells to counteract neurodegeneration. The pathological environment characteristics such as magnitude of inflammation play a critical role in the survival of, differentiation, and function of both grafted and endogenous cells. Stem cells actions together with their progeny underlying the behavioural recovery in animal models are well understood as compared to few years ago. Regardless of cell replacement, stem cells have been also found to champion in the improvements that could have clinical value through immunomodulation, trophic actions, together with stimulation of angiogenesis. These are essential advancements in stem cell studies that would result into massive scientifically justified clinical trials in neurodegenerative diseases within the next couple of years. The direct conversion from differentiated cells into specific cells is now possible through different improved technologies. For instance, direct reprogramming of human fibroblasts into dopaminergic neurons that have neuronal transcriptions factors is possible. For this reason, AD patient fibroblasts can be converted into functional neurons and thus there is possibility of direct reprogramming as an alternative disease model. Similarly, motor neurons can be generated using the direct reprogramming approach. The capacity for iPSCs to treat patients suffering from neurodegenerative diseases is immense. For instance, induced stem cells can directly be introduced into clinical applications in a myriad of ways including disease modelling, drug screening, as well as cell replacement therapy. The challenges encountered here are ensuring the clinical safety, which must be overcome for this work out conveniently. References Bertram L, and Tanzi RE. 2005. 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