Stem Cell Treatment for Parkinsons Disease to Produce Dopaminergic Neurons - Annotated Bibliography Example

Stem Cell Treatment for Parkinson’s Disease to Produce Dopaminergic Neurons Key Words Dopamine Dyskinesia Embryonic stem cells Fetal stem cells Levodopa Mesenchymal stem cells Neurons Stem cells Transplantation Acronyms AADC – aromatic L-amino acid decarboxylase AAV – adeno-associated virus BM-MSCs – bone-marrow-derived mesenchymal stem cells DA – Transplanted midbrain dopamine neurons Dopamine neurons hESC – human embryonic stem cells hMSCs – human hematopoietic and mesenchymal stem cells hNSCs – human neural stem cell line hPSCs – human pluripotent stem cells L-DOPA – dihydroxyphenyl-L-alainine MSCs – marrow stromal cells PD – Parkinson’s disease SNpc – Substantia Nigra pars compacta SVZ – subventricular zone TH – tyrosine hydroxylase Introduction One of the latest insights from research studies in Parkinson’s disease is the potential of stem cells in treating the disease. Cova et al., (2010) stated that despite the current controversies regarding the regenerative capacity of pathological CNS, there is hope in endogenous repair will be a suitable alternative for PD treatment. Apparently, these research studies have shown laboratory-produced stem cells that produce dopamine can be used to treat Parkinson’s patients by replacing the damaged neurons with these laboratory manufactured ones. The basis of these studies is the fact that scientists know which particular cells within the brain are affected by Parkinson’s disease. Specifically, scientists have established that PD affects specific neurons that produce dopamine in the brain. Since the disease kills these dopamine producing neurons, stem cells provide a potential solution for replacing the dopamine producing neurons. Scientists can use specific stem cells to produce dopamine-producing neurons in vitro. Kriks et al., (2011) stated that engaftable DA neurons can survive in vitro for months. Through previous stem cell studies, researchers have established the embryonic and fetal neurons can be used to reverse the effects of PD on the dopamine producing neurons in the brain. This enables them to study the disease in depth. Moreover, the laboratory produced cells can them be introduced into the affected PD patients such that they replace the damaged ones and cause a reversal of the Parkinson’s disease. These studies are yet to be conducted on humans because of the uncertainties and side effects realized. However, their findings provide hope that stem cells can provide the much needed treatment for Parkinson’s disease. This paper presented an annotated bibliography of 10 research papers on the subject of stem cell treatment for Parkinson’s disease to produce dopaminergic neurons.The research studies present various findings that support the potential of stem cell treatment for PD to produce dopaminergic neurons, which are killed by the disease. However, the studies also present other findings related to the potential and efficiency of stem cell treatment for PD. Cova, L., Armentero, M., Zennaro, E., Calzarossa, C., Bossolasco, P. et al. 2010.‘Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson’s disease.’Brain Research, vol. 1311, pp. 12-27. The purpose of this study was to explore the neurogenic as well as the neurorescue potential of hMSCs in the treatment of PD. The researchers used a rodent sample to conduct the study. Of particular interest in the study were two regions in the brain, SNpc and SVZ. These two regions are connected to the striatum by the dopaminergic afferents. The study generated two main findings. First, the researchers established that transplanting of hMSCs triggers neurogenesis, which suggests that stem cells can actually produce dopaminergic neurons to replace the lost ones in the brain. This implies that stem cell thepray with hMSCs can reverse the effects of PD. Second, the researchers established that hMSCs protect dopaminergic neurons. This suggests that hMSCs can actually prevent proliferation of PD by protecting the dopaminergic neurons. Using hMSCs transplants can actually be an effective prevention and treatment for PD. If used on patients with advanced PD, hMSCs can reverse the loss of dopamine neurons. If used on patients in early stages of PD, hMSCs could actually prevent further loss of the dopamine neurons. Daadi, M. M., Grueter, B. A., Malenka, R. C., RedmondJr, D. E., & Steinberg, G. K. 2012,‘Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson’s disease’,PloS one, vol. 7, no. 7, pp. 1-11. Daadi et al., (2012) studied the effect of dopaminergic neurons derived from hESCs on treatment of PD and related neurological disorders. Specifically, the study derived hNSCs from the hESCs and used transplanted them into monkey models for PD. The extraction of hNSCs from the hESCs was conducted in vitro in a culture medium. The hNSCs were then transplanted into the substantia nigra and caudate of the monkey models. After a period of two months, about 10 per cent of the transplanted hNSCs depicted dopaminergic phenotype. The study further established that the transplanted hNSCs showed neurite outgrowths but lacked serotonin expression. From these findings, we can deduce that DA-induced neurons are able to engraft effectively in the midbrain and express similar characteristics as dopaminergic neurons in brain. The study supports the possibility of using hESCs in the stem cell therapy for PD. The basis of this study is the ability of hESCs to mimic the characteristics of dopamine neurons in the brain. Grealish, S., Diguet, E., Kirkeby, A., Mattson, B., Heuer, A., et al. 2014. ‘Human ESC-derived dopamine neurons show similar preclinical efficacy and potency for fetal neurons when grafted in a rat model of Parkinson’s disease.’ Cell Stem Cell, vol. 15, no. 5, pp. 653-665. In this study, Grealish et al (2014) perform a preclinical test of the functionality of hESC or human embryonic stem cells in the treatment of Parkinson’s disease. The researchers use animal tests, specifically rats, to perform their study because of the uncertainty involved in human effects of such studies. From their study, the researchers find out that hESC is functional in the long-term in the restoration of dopamine neurons within the brain that have been killed by Parkinson’s disease. This finding concurs with that of Hallet et al., (2014) in supporting the use of stem cell transplants in treatment of Parkinson’s disease. However, Grealish et al. (2014) go further in showing the hESC are equally functional as fetal dopaminergic neurons in the treatment of the disease.Stem cell treatment of PD could be use either embryonic (hESC) or fetal dopaminergic neurons. The two types of dopaminergic neurons have the same effect on PD treatment and prevention. Hallett, P., J., Cooper., O., Sadi, D., Robertson, H., Mendez, I., et al. 2014. ‘Long-term health of dopaminergic neuron transplants in Parkinson’s disease patients.’ Cell Reports, vol. 7, no. 6, pp. 1755-1761. Hallet et al. (2014) conducted this study with the purpose of determining the long-term health effect of dopaminergic neurons that are transplanted in patients with Parkinson’s disease. The main finding from the study was that transplanted dopaminergic neurons actually function for an extended period of up to 15 years. This finding supports the view that stem cell treatment with fetal dopaminergic neurons is effective in treating Parkinson’s disease. The researchers found out that the transplanted fetal neurons were actually functional for an extended period. This finding shed more light on the longevity of transplanted dopaminergic neurons on PD patients. The study findings suggest that the long term health of PD patients is enhanced through the use of dopaminergic neurones and transplanted fetal neurones. This is because of the replacement of the lost dopamine neurons in the patients’ brain that had worsened their health condition. The study provides more evidence for the adopting of cell stem treatment for this disease. Kriks, S., Shim, J. W., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., ... & Studer, L. 2011, ‘Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson/s disease’, Nature, vol. 480, no. 7378, pp. 547-551. Kriks et al. (2011) conducted a study on rodents and monkeys to determine the efficiency of human DA neurons engrafting in vivo. The findings from the study show that it is possible to engraft the human DA neurons in vivo efficiently in the treatment of PD. However, the study reveals that previous problems of using hPSCs in the treatment of PD are largely based on the improper extraction of DA neurons from these hPSCs. By extracting the right DP neurons, the efficiency of hPSCs in treatment of PD could be high. Kirk et al. (2011) also focused on scalability of the findings by using monkeys instead of rodents. The experiments on the monkeys showed that the efficiency of human DA generated from hPSCs could be scaled for human PD patients. This study addresses some of the concerns emanating from previous studies that showed DA neurons from hPSCs to be less efficient in treating PD. Apart from proving hPSC to be an potential source of DA neurons for treatment of PD, the study also showed that using DA neurons from hPSC was not likely to cause harmful effects such as neural overgrowth and teratoma formation. Kurowska, Z., Englund, E., Widner, H., Lindvall, O., Li, J. Y., &Brundin, P. 2011, ‘Signs of degeneration in 12–22-year old grafts of mesencephalic dopamine neurons in patients with Parkinsons disease’,Journal of Parkinsons disease, vol. 1, no. 1, pp. 83-92. Kurowska et al. (2011) conducted an empirical research to determine the survival of grafted human fetal neurons. The research focused on three human models including a PD patient with a 22 year old DP graft, one with 16 year old graft, and another with a 12 year old graft. The researchers focused on the morphological features of the neurons and compared these features among the three PD patients. One of the findings showed that the younger DP grafts expressed more dopamine transporter and tyrosine hydroxylase than the older graft. A similar trend was seen in the expression of α-synucleinimmunoreactivity. Based on these findings, the study concluded that the gtafted neurons degenerated with time. Apart from supporting the effectiveness of dopaminergic neurons grafts in treating PD, the study also shows that the grafted neurons have a longer lifetime extending over two decades. However, the effectiveness of the grafted neurons continuous to depreciate over time. Muramatsu, S, Fujimoto, K, Kato, S, Mizukami, H, Asari, S, Ikeguchi, K, Kawakami, T, Urabe, M, Kume, A, Sato, T, Watanabe, E, Ozawa, K, & Nakano, I 2010, A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinsons disease, Molecular Therapy: The Journal Of The American Society Of Gene Therapy, vol. 18, no. 9, pp. 1731-1735. Muramatsu et al (2010) conducted a study to establish the tolerability, efficiency, and safety of vector-mediated gene therapy on treating PD among a sample of six PD patients. The researchers used AAV as the vehicle for delivery of the AADC in to the patients’ putamen. AADC is responsible for the synthesis of dopamine. Although the researchers had previous knowledge of the effective use of gene therapy in treating PD among animal samples, they were interested in determining the tolerability, safety, and efficacy of using AAV to transmit the AADC into the PD patients. The findings revealed insignificant toxicity of AAV mediated AADC transplanting on the sample population. With regard to safety, the findings also showed that this procedure was safe. With regard to efficacy, the findings revealed an improved motor performance among the PD patients, which implies that it passed the efficacy test. The study suggests that selecting the appropriate gene vector is important in stem cell treatment of PD. Politis, M., Oertel, W. H., Wu, K., Quinn, N. P., Pogarell, O., Brooks, D. J., ... &Piccini, P. 2011, ‘Graft‐induced dyskinesias in Parkinsons disease: High striatal serotonin/dopamine transporter ratio’,Movement Disorders, vol. 26, no. 11, pp. 1997-2003. Politis et al. (2011) conducted a longitudinal study on a PD patient who had received treatment with fetal grafts as well as brain stimulation. After a period of 14 years since the fetal grafting, the patient showed conflicting outcomes. With regard to motor symptoms, the patients depicted noticeable improvement. However, the patient continued to experience dyskinesias, which was linked to the fetal graft. Through a series of imaging and clinical assessments, it emerged that the serotonin/dopamine transporter ratio within the patient’s grafted striatum had elevated. After the patient was administered with a 5-HT1A agonist, the dyskensias was suppressed. Apparently, the 5-HT1A agonist inhibited the activity of serotonin neutron. These findings have two main implications for the treatment of PD through stem cell therapy. First, the improved motor symptions in the PD patient suggest that stem cell therapy is effective in treating PD. Second, the study shows that it is possible to prevent the development of graft-induced dyskinesias in stem cell treatment of PD. Politis, M., Wu, K., Loane, C., Quinn, N. P., Brooks, D. J., Oertel, W. H., ... &Piccini, P. 2012, ‘Serotonin neuron loss and nonmotor symptoms continue in Parkinson’s patients treated with dopamine grafts’, Science translational medicine, vol. 4, no. 128, pp. 1-10. Politis et al. (2012) investigated three PD patients with fetal grafts of between 13 and 16 years to establish why they did not show improvement in nonmotor symptoms associated with PD including sleep problems, depression, visual hallucination, and fatigue. Using imaging technologies such as positron emission tomography, the researchers checked effects of the fetal grafts on the patients. With regard to dopamine neurone function, the study revealed that the fetal grafts were effective in restoring the DP function. This explained the improvement in motor symptoms in the patients. However, the study also revealed that fewer serotonin neurons were present in parts of the brain associated with regulation of mood, sleep, arousal, emotion, and satiety. This finding implies that the DP fetal grafts may not be effective in treating nonmotor PD symptoms. However, the study suggests that stem cells containing both dopamine neurons and serotonin neurons could have better outcomes in treating motor and nonmotorsymptions of PD. Venkataramana, N., K., Kumar, S., V., Balaraju, S., Radhakrishnar, R., C., Bansal, A., et al. 2010. ‘Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease.’ Translational Research, vol. 155, no. 2, pp. 62-70. Venkataramana et al., (2010) conducted this study to determine the feasibility and safety of stem cell treatment in Parkinson’s patients. The researchers specifically focused on how transplants of BM-MSCs on seven PD patients performed. The findings showed some improvement in the symptoms exemplified by the patients, which means that the BM-MSCs were probably feasible in regenerating the dopaminergic neurons that had been killed by the disease. Additionally, the researchers found no harmful side effects of the BM-MSCs on the PD patients, which suggests that such stem cell treatment could be safe to use. Overall, the findings from the study point to the possibility of stem cell transplanting in the treatment of PD. However, Venkataramana et al., (2010) are quick to note the limitations in their study and recommend additional research to address them. Nevertheless, the findings from the study provide relevant insights regarding the use of stem cell treatment in replacing dopaminergic neurons in PD patients. Conclusion Stem cell treatment of PD is gaining more momentum from various research studies that are showing positive outcomes. Through animal models and human models in some instances, these studies have shown that dopaminergic neurons produced in vitro can actually halt the destruction of dopamine neurons in the brain as a result of PD. This halting effect implies that stem cell treatment can actually prevent the worsening of PD among patients. Apart from preventing the worsening of PD patients’ conditions, stem cell studies have shown that dopaminergic neurons, including embryonic and fetal neurons, can replace the lost dopamine neurons in the brain. This finding suggests that stem cell treatment can actually reverse PD. Other studies have also shown that dopaminergic neurons transplanted into the brain of PD patients can last for extended periods of up to 15 years. This suggests that stem cell treatment could have the potential to offer long-term treatment for PD patients. Additionally, different studies on the effectiveness and efficiency of gene vectors in stem cell treatment have shown that certain gene vectors such as AAV and MSCs in the transplanting of AADC and TH genes to the brain are highly effective and efficient. Despite the positive findings from these research studies, there are still many limitations and gaps towards the full adoption of stem cell treatment of PD. One of the main limitations is the uncertainty regarding the potential adverse effects of such treatment on PD patients. Another limitation is about the efficiency of using gene vectors in transplanting dopaminergic neurons to the brain. Some studies have shown that the efficiency is not 100 per cent. As The duration of transplanted dopaminergic neurons in the brain is also not very clear. Before stem cell treatment is fully adopted for treatment of PD, these and other concerns will have to be addressed. Daadi et al., (2012) stated that the findings from their study opened the way for further studies into the in vivo functionality of various sources of doparmingergic neurons to identify the most effective in treatment of PD. References Cova, L., Armentero, M., Zennaro, E., Calzarossa, C., Bossolasco, P. et al. 2010, ‘Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson’s disease’, Brain Research, vol. 1311, pp. 12-27. Daadi, M. M., Grueter, B. A., Malenka, R. C., RedmondJr, D. E., & Steinberg, G. K. 2012,‘Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson’s disease’,PloS one, vol. 7, no. 7, pp. 1-11. Grealish, S., Diguet, E., Kirkeby, A., Mattson, B., Heuer, A., et al. 2014, ‘Human ESC-derived dopamine neurons show similar preclinical efficacy and potency for fetal neurons when grafted in a rat model of Parkinson’s disease’, Cell Stem Cell, vol. 15, no. 5, pp. 653-665. Hallett, P., J., Cooper., O., Sadi, D., Robertson, H., Mendez, I., et al. 2014, ‘Long-term health of dopaminergic neuron transplants in Parkinson’s disease patients’, Cell Reports, vol. 7, no. 6, pp. 1755-1761. Kriks, S., Shim, J. W., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., ... & Studer, L. 2011, ‘Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson/s disease’, Nature, vol. 480, no. 7378, pp. 547-551. Kurowska, Z., Englund, E., Widner, H., Lindvall, O., Li, J. Y., &Brundin, P. 2011, ‘Signs of degeneration in 12–22-year old grafts of mesencephalic dopamine neurons in patients with Parkinsons disease’,Journal of Parkinsons disease, vol. 1, no. 1, pp. 83-92. Muramatsu, S, Fujimoto, K, Kato, S, Mizukami, H, Asari, S, Ikeguchi, K, Kawakami, T, Urabe, M, Kume, A, Sato, T, Watanabe, E, Ozawa, K, & Nakano, I 2010, A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinsons disease, Molecular Therapy: The Journal Of The American Society Of Gene Therapy, vol. 18, no. 9, pp. 1731-1735. Politis, M., Oertel, W. H., Wu, K., Quinn, N. P., Pogarell, O., Brooks, D. J., ... &Piccini, P. 2011, ‘Graft‐induced dyskinesias in Parkinsons disease: High striatal serotonin/dopamine transporter ratio’,Movement Disorders, vol. 26, no. 11, pp. 1997-2003. Politis, M., Wu, K., Loane, C., Quinn, N. P., Brooks, D. J., Oertel, W. H., ... &Piccini, P. 2012, ‘Serotonin neuron loss and nonmotor symptoms continue in Parkinson’s patients treated with dopamine grafts’, Science translational medicine, vol. 4, no. 128, pp. 1-10. Venkataramana, N., K., Kumar, S., V., Balaraju, S., Radhakrishnar, R., C., Bansal, A., et al. 2010, ‘Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease’, Translational Research, vol. 155, no. 2, pp. 62-70. Read More