Neuroscience and cell biology

Question: Discuss about the potential of neuroprotective and cell-replacement therapies as Disease modifying therapies for Parkinson's diseas? Answer: Introduction Parkinson disease is the neurodegenerative disease. This common disease affects people over 65 years age (Buttery and Barker 2014). The disease is characterised by progressive degeneration of the dopaminergic neurons that leads to disability of movement. It is due to presence of alpha-synuclein positive Lewy bodies in the substantia nigra. Lewy bodies are identified to be associated with the non-motor features of the disease such as sleep, cognitive an autonomic dysfunction. Among most restorative therapies to the disease are neuroprotective factor therapy and cell replacement therapy. Experiments with this approaches showed promising results. The paper discusses the potential of neuroprotective and cell-replacement therapies as disease modifying therapies (alternative to drug therapy) for Parkinson's disease. Discussion According to Barrow (2015) stem cell therapy has been found to have exciting prospects in treatment of Parkinsons disease. It has been effective in treating several neurodegenerative conditions. Some of the experiment with high potential to treat parkinsons disease have been discussed below. In patients with this disease, the central nervous system or CNS does not regenerate its own neurons. Hence, stem cells are a good choice as they have pluripotency. Initiating the differentiation of the stem cells under correct conditions will help generate dopminergic neurons, which can then be transplanted into the patients for replacing their dopamine levels. Both Michael J Fox Foundation and Parkinson's UK actively research into potential stem cells therapy (Kim et al. 2002). Kriks et al. (2011) showed that in an animal model of Parkinsons disease, when dopamine neurons extracted from the embryonic stem cells were transplanted it showed to function effectively. These neurons have ability to efficiently engraft in the animal model. There was an improvement in dopaminergic delivery to the neighbouring parts when these neurons got established within the striatum. It aids in improving the motor control and preventing the worsening symptoms of the illness. Induced pluripotent stem cells or iPS have properties same as ESCs. They can be derived from adult human dermal fibroblasts. iPSs has obvious potential for Parkinsons disease as cell based therapy (Canet-Aviles et al. 2014). However, eliminating their tumour inducing property will make them highly suitable for cell therapy. It is devoid of ethical problems as the iPSs can be derived from pateints own adult cells and there is no risk of rejection. The cell line of iPS called IMR90clone 4 is available which can be differentiated into dopaminergic neuron progenitors. Upon transplanting it into the rat disease model these progenitors were found surviving for a very long period. In other experiment iPSs having point mutation in -synuclein (A53T) were developed for the disease. After transplantation the mutation was reversed via zinc finger nuclease genetic editing successfully. Later functional dopaminergic neurons were generated (Pawitan 2011). Other potential method of cell replacement therapy is the implantation of the neural stem cellsor NSC into the striatum of the effected patients (Buttery and Barker 2014). With the help of the extracellular signalling, these cells were differentiating into dopaminergic neurons as a response to the host body signals. An intrinsic ability of NSCs is to generate neuroprotective factors by influencing the CNS. However, there is a need of providing appropriate in vitro signalling. It was evident from the study that the adult stem cells have higher potential than the embryonic stem cells. Additional advantage of the adult stem cells is that it can be extracted from other sources such as oral mucosa, adipose tissue and bone marrow. It does not depend on the aborted foetal tissues. This potential therapy was successful when applied to Mr. Dennis Turnerin the USA. He was a patient of Parkinsons for 14 years and he himself have declared the benefits of cell replacement therapy. The most promising disease modifying therapy for Parkinsons disease is Neuroprotection and neuroregeneration. As per Lu-Nguyen et al. (2014) the Neurotrophic factors have the potential to act as disease modifying treatment among the current research strategies as they play significant regulatory role in the development, and survival of specific populations of neurons. They can also reverse the loss of nigrostriatal dopaminergic neurons. The main cause of symptoms in Parkinsons disease is the on-going degeneration. Therefore, trials were conducted to halt the degeneration process. Experiments using the neuropreotective agents such as glial cell-line derived neuropreotective factor or GDNF showed promising results. However, the potential for targeted delivery is yet to be achieved which otherwise may result in adverse effects due to off-target response. Experiments on mice model and on 5 people in advance stage disease in phase 1 trial gave promising results after 2 years. In these pat ients with GDNF was delivered by pump bilaterally into dorsalputamen. Patients were found with bilateral improvement. However, there remains a scientific challenge of applying the Neurotrophic factors to enhance cell survival for in vivo or ex vivo gene therapy. Current trial with AAV2 using convection-enhanced delivery with dose escalation is expected to meet six months primary outcomes. Another trial including the delivery of neurturin on 12 patients in phase 1 showed high potential after 1 year in 2008 in treating parkinsons disease. Next trial in 2015 using convection-enhanced delivery confirmed safety of nigra after dlivery. Delivery of neurturin using AAV2 vector (CERE-120) into stratum and ventral midbrain enhanced the neuroprotection in PD models and seems necessary alternate approach (Herzog et al. 2013). Conclusion It can be concluded from the above discussion that there are variety of cells having the ability to differentiate into cells that produce neurotrophic factor or dopaminergic neurons. The literature review shows that most experiments that have given promising results were conducted in animal models showing high efficacy. Some of the experiments have been used in human trials. Efficacy and safety assurance is required for translation into human therapy. Future experiments needs to be performed using standardized procedure for each type of Parkinson's disease, kind of cell effected, and the delivery site. Sustainable therapeutic effect may be achieved by the modulation of microenvironment for increasing the efficacy. References Barrow, T.R., 2015. Cell replacement therapy in Parkinson's disease.Bioscience Horizons: The National Undergraduate Research Journal,8. Buttery, P.C. and Barker, R.A., 2014. Treating Parkinson's disease in the 21st century: can stem cell transplantation compete?.Journal of Comparative Neurology,522(12), pp.2802-2816. Canet-Aviles, R., Lomax, G.P., Feigal, E.G. and Priest, C., 2014. Proceedings: Cell Therapies for Parkinson's Disease From Discovery to Clinic.Stem cells translational medicine,3(9), pp.979-991. Hegarty, S.V., O'keeffe, G.W. and Sullivan, A.M., 2014. Neurotrophic factors: from neurodevelopmental regulators to novel therapies for Parkinson's disease.Neural regeneration research,9(19), p.1708. Herzog, C.D., Brown, L., Kruegel, B.R., Wilson, A., Tansey, M.G., Gage, F.H., Johnson, E.M. and Bartus, R.T., 2013. Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120).Neurobiology of disease,58, pp.38-48. Kim, J.H., Auerbach, J.M., Rodrguez-Gmez, J.A., Velasco, I., Gavin, D., Lumelsky, N., Lee, S.H., Nguyen, J., Snchez-Pernaute, R., Bankiewicz, K. and McKay, R., 2002. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.Nature,418(6893), pp.50-56. Kriks, S., Shim, J.W., Piao, J., Ganat, Y.M., Wakeman, D.R., Xie, Z., Carrillo-Reid, L., Auyeung, G., Antonacci, C., Buch, A. and Yang, L., 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson/'s disease.Nature,480(7378), pp.547-551. Lu-Nguyen, N.B., Broadstock, M., Schliesser, M.G., Bartholomae, C.C., von Kalle, C., Schmidt, M. and Yez-Muoz, R.J., 2014. Transgenic expression of human glial cell line-derived neurotrophic factor from integration-deficient lentiviral vectors is neuroprotective in a rodent model of Parkinson's disease.Human gene therapy,25(7), pp.631-641. Pawitan, J.A., 2011. Prospect of cell therapy for Parkinson's disease.Anatomy cell biology,44(4), pp.256-264.