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Cell replacement therapy in Parkinson's disease

Cell replacement therapy in Parkinson's disease BioscienceHorizons Volume 8 2015 10.1093/biohorizons/hzv002 Review article Tom Robert Barrow* Imperial College London, South Kensington, London SW7 2AZ, England *Corresponding author: 102 Rannoch Road, Hammersmith, London W6 9SW, England. Email: tom.barrow10@imperial.ac.uk Supervisor: Dr Jane L. Saffell, Imperial College London, South Kensington, London, SW7 2AZ, England. With an ageing population, the incidence of Parkinson’s disease is increasing. The disease has an overwhelming impact on those it affects and has a limited repertoire of drug therapies available, each with problematic side effects. Stem cell therapy is an exciting prospect in the treatment of several neurodegenerative conditions. This article takes an in depth look at the great potential of cell replacement therapy for Parkinson’s disease, providing supporting evidence for investment in this potential treatment. After considering the basis for cell replacement therapy, the article looks at stem cells of different origins, summing up the strengths and limitations of each in relation to Parkinson’s disease. In addition to highlighting the cell replace- ment therapies available, the article also provides a chronology of research into this emerging field over the last 30 years. Key words: Parkinson’s disease, stem cells, cell replacement therapy, stem cell transplant, regeneration, clinical trials Submitted on 24 August 2014; accepted on 16 February 2015 Introduction What is PD? In 1984, Muhammad Ali, the former heavyweight champion In 1817 James Parkinson documented six cases he had been of the world, was diagnosed with Parkinson’s disease (PD); observing in ‘An Essay on The Shaking Palsy’, describing the he began to experience tremors and a slowness in his move- classic motor symptoms of the disease that now bears his ments, known as bradykinesia. After years of battling with name and establishing it as a medical condition (Parkinson, the disease, Ali now has difficulty speaking and coordinating 1817). Today there is a greater understanding of the underly- his movements but remains an inspiration to many (The ing causes of these symptoms. However, what triggers degen- Guardian, 2009; Tim Dahlberg, The Seattle Times, 2012). eration of the dopaminergic neurons in the first place remains PD affects around 6.3 million people worldwide, with most unknown. Only 5% of PD cases can be attributed to specific diagnoses being made over the age of 60. It is currently an heritable genes such as PARK1, a gene responsible for encod- incurable disease associated with irreversible loss of the ing the neural protein α-synuclein (Dawson and Dawson, dopaminergic neurons in the substantia nigra (SN) and stria- 2003), the remaining 95% are idiopathic. Diagnosis of PD is tum, which are structures of the basal ganglia, essential for still a clinical diagnosis based on the four cardinal symptoms, fine motor control and initiation of movement ( Barker, as there is no definitive test. Symptoms become apparent once Cicchetti and Neal, 2012). As the central nervous system over 80% of the dopaminergic neurons have been lost (Miller (CNS) has a limited capacity to regenerate its neurons, this and O’Callaghan, 2014). On post-mortem examination, the has a devastating effect on motor function. Consequently, the SN of PD patients has a pale appearance. This is because four hallmark symptoms of PD are rigidity , tremor at rest, dopaminergic neurons are rich in neuromelanin, the substance bradykinesia and postural instability. Current drug therapies that gives rise to the dark pigmentation of the SN in normal target symptom management, and at present there are no adults (Zecca et al., 2003). Under a microscope abnormal cures for PD. This begs the question, is there potential for a aggregates of protein can be seen, known as Lewy bodies. treatment in the future and how does cell replacement ther- The specific cause of idiopathic PD is uncertain, it is likely to apy fit into the picture? be a combination of genetic and environment influences. © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  Review article Bioscience Horizons • Volume 8 2015 For instance, MPTP exposure, a compound initially synthe- The idea of treating PD using cell replacement therapy is sized as a narcotic, induces symptoms of PD. This demon- not a new one; research in this area started in the early 1990s. strates the potential of environmental toxins having a role and Studies investigating the effects of foetal neuronal tissue in PD has provided one of the principal animal models of PD (Sian patients yielded promising results. A study published in 1994, et al., 1999). The two leading theories for the pathogenesis of transplanted foetal ventral mesencephalic tissue (which would PD centre around the aggregation of misfolded proteins (such later develop into the basal ganglia) rich in dopaminergic neu- as α-synuclein) and oxidative stress caused by mitochondrial roblasts (precursors) from aborted foetuses into the striatum dysfunction (Dauer and Przedborski, 2003). of two patients with idiopathic PD (Peschanski et al., 1994). The team followed up the patients and compared PET scan data of Flurodopa (dopamine with a radioactive isotope) with Current drug therapy motor changes. The results showed an increase in Flurodopa uptake at the site of grafting along with improved motor per- As PD is caused by a loss of the dopaminergic neurons, the formance in both patients. This study demonstrated that neu- main drug therapies focus on replenishing the dopamine ral transplantation was a possibility and was a step in the within the basal ganglia. By replacing the dopamine, motor right direction for cell replacement therapy; it showed that symptoms are reduced, and this has a significant impact on transplanted dopaminergic neurons could survive and re- patients’ quality of life. Dopamine precursors such as innervate the striatum. A number of studies reached the same Levodopa and dopamine agonists form the basis of current conclusions, adding strength to the potential of cell replace- therapy. Levodopa is augmented with a DOPA decarboxylase ment therapy as a treatment for PD (Hoffer et al., 1992; inhibitor to reduce peripheral conversion, ensuring the Defer et al., 1996; Levivier et al., 1997). majority of Levodopa is converted to dopamine within the CNS (Poewe and Antonini, 2014). Monoamine oxidase B These studies also demonstrated some of the limitations inhibitors can also be prescribed to reduce the breakdown of with transplantation of foetal tissue. One study retrospec- dopamine within the brain. While these drugs initially relieve tively followed up 14 patients who had received a graft of patients of their symptoms, their therapeutic benefit dimin - foetal mesencephalic tissue; the results showed that a number ishes with time. This is known as ‘wearing off’ and means of subjects suffered from graft-induced dyskinesias (Hagell patients require a higher dose to experience the same benefit et al., 2002). The mechanism behind this was not fully under- (Stocchi, 2006). Unfortunately, these drugs also have unpleas- stood, although it was hypothesized that the side effects ant side effects such as dyskinesia, which is the occurrence of could be due to dopamine reaching over-sensitized receptors involuntary movements. Although medication is the main- or due to the non-dopaminergic portions of the graft. It must stay of PD management, there are alternative treatments such also be appreciated that while these transplants demonstrated as speech and language therapy or surgical options such as the promising potential of cell replacement therapy, it is not a deep brain stimulation (DBS) (Odekerken et al., 2013). clinically viable model to use foetal tissue to treat PD patients. Current therapies have their limitations as they focus on It would be ethically questionable to use aborted foetal tissue symptomatic relief only and do nothing to reverse or slow as a treatment and require more than can be realistically down the progression of the disease. As PD is caused by sourced. degeneration of dopaminergic neurons, it stands to reason that differentiated stem cells could be implanted to replace Embryonic stem cells lost neurons and consequently re-innervate the striatum. Following the encouraging results of foetal tissue grafts, The case for cell replacement embryonic stem cells (ESCs) became the focus of research therapy into cell replacement therapy. Stem cells could provide the perfect source for neuronal replacement; ESCs are derived Cell replacement therapy is a promising avenue into the from the inner cell mass of the blastocyst and are pluripotent investigation and treatment of neurodegenerative diseases. with the ability to proliferate extensively. The CNS is unable to regenerate its own neurons, due to the physical and chemical barriers formed by glial scars (Ohtake A study looking at the effect of transplanting a low dose of and Li, 2014). Stem cells have the ability to multiply and dif- mouse ESCs to OHDA-lesioned (neurotoxic compound ferentiate down any cell line, this is known as pluripotency. which targets dopaminergic neurons) rats showed that the Current research is focussing on the pluripotent potential of naïve cells developed into functional dopaminergic neurons various forms of stem cells. By inducing stem cells to differ- in some cases (Bjorklund et al., 2002). Using PET scans and entiate under the correct conditions, dopaminergic neurons quantitative measurements of rotational behaviour in can be created. These neurons can be transplanted into a response to amphetamines, rats with ESC-derived dopami- patient with PD, replacing their dopamine levels and provid- nergic neurons showed some gradual but significant improve - ing symptomatic relief. Both the Michael J Fox Foundation ment of symptoms. However, this study also highlighted and Parkinson’s UK refer to stem cell therapies on their web- some unfavourable side effects. The study had a high rate of sites and actively back research into this potential therapy. tumour formation and graft failure. Of the 25 rats that 2 Bioscience Horizons • Volume 8 2015 Review article received the transplants, 6 showed no ESC survival and 5 neural stem cells, found in the subventricular zone and hip- died of teratoma-like tumours (Bjorklund et al., 2002). While pocampus, could be used in a similar way (Clarke et al., the study yielded some positive results, the high incidence of 2000). By implanting these neural stem cells (NSCs) into the tumour formation indicates some of the risks involved in striatum of PD patients, extracellular signalling might influ - transplanting highly proliferative tissues. ence their differentiation and form dopaminergic neurons. Another study published in Nature followed a similar A study conducted in 2002 implanted NSCs unilaterally procedure; here they looked at stimulating the differentia- into MPTP-treated mice (animal PD model). Following this, tion of ESCs into dopaminergic neurons in vitro before it was observed that some mice began rotating in the opposite transplanting these into an animal model of PD (Kim et al., direction to the implantation. An amphetamine challenge 2002). The results showed that the grafted ESC-derived neu- (causing DA release) and later histological evidence were rons survived and proved to be functional. However, the used to confirm that this was due to the implanted NSCs. study agreed that tumour formation was an unacceptable Although it was found that some of the transplanted cells complication associated with ESC grafts and that further differentiated into dopaminergic neurons, surprisingly it was animal studies were required to understand the safety and discovered that the majority of the dopaminergic neurons efficacy of these transplants. present were ‘rescued’ host cells (Ourednik et al., 2002). It was hypothesized that NSCs have an intrinsic ability to pro- Recent studies have since had mixed results in animal duce trophic (survival/growth) and neuroprotective factors models. However, improvements in culture methods and dif- sufficient to save damaged cells. The study demonstrated that ferentiation protocol have succeeded in creating a more NSCs migrated readily throughout the striatum, particularly homogenous and scalable population of dopaminergic neu- in the aged brain; here they were able to differentiate into rons (A9-type) specific to the ventrolateral and caudal regions dopaminergic neurons in response to host signals. In addi- of the SN. Animal models have subsequently seen improved tion, it showed the potential of NSCs to influence the existing outcomes, which correlates with evidence of increased fibre CNS, rescuing the present neurons and recovering the striatal outgrowth. Although, there is still concern as the potential dopaminergic system (Ourednik et al., 2002). for abherrant inervation and graft-induced dyskinesias remains unknown. It is hypothesized that genetic modifica - It is worth noting that adult stem cells can be derived from tion of these implanted neurons might be able to limit exces- sources other than the brain, which requires an invasive sive outgrowth (Ambasudhan et al., 2014). A number of biopsy. For instance, studies have demonstrated that stem techniques have been suggested to minimize the risk of cells can be harvested from the oral mucosa, endometrium, tumour formation; these include prolonged pre-differentia- bone marrow and adipose tissue. Given appropriate in vitro tion of ESCs, selection of differentiated cells for transplanta- signalling, these cells have the potential to differentiate into tion and genetic engineering to block tumourigenic pathways dopaminergic neurons and have also proven to be effective (Ambasudhan et al., 2014). when implanted into animal models of PD (Berg et al., 2014; Ganz et al., 2014; Wolff et al., 2015). The potential therapeutic use of ESCs and the possible complications are clearly demonstrated by these studies. As This demonstrates the promising advantages of adult stem with foetal tissue implants mentioned earlier, they hint cells compared with ESCs. Alongside showing similar regen- towards the intriguing potential for a method of regenerating erative potential in early trials, adult stem cells could be lost dopaminergic neurons in PD patients. Unfortunately, extensively cultured and potentially stimulated to differenti- they also demonstrate how far cell replacement therapy is ate in vitro. Another benefit of adult stem cells is that it does from being an operational procedure for PD patients. As with not depend on aborted foetal tissue, making it less ethically tissue implants, similar limitations apply. Both models require ambiguous, it also means there is a readily available self- immunosuppression to prevent graft rejection, and ESC derived source. It seems reasonable that with an appropriate transplants are associated with tumour formation. Supply of method, stem cells could be harvested, cultured, treated and ESCs is also limited and once again poses complicated ethical subsequently implanted into the striatum, overcoming the questions. issue of graft rejection. This potential therapy was carried out on Mr Dennis Adult stem cells Turner in the USA: after suffering from PD for 14 years and While ESCs provide promise for the future of PD treatment, experiencing severe symptoms, he received a transplant of his as a basis for cell replacement therapy the resources are lim- own NSCs that had been cultured and matured into dopami- ited. Interestingly, it has been discovered that adults also have nergic neurons from cortical tissues (Lévesque, Neuman and regions of undifferentiated, self-renewing stem cells. For Rezak, 2009). Mr Turner testified at a US Senate Committee instance, haematopoietic cells found in bone marrow are meeting in 2004 (Congressional Record, 2007) as an advo- precursors for all blood cell types in the body; these stem cate for the funding of research into treating PD using cell cells have been used successfully in transplants for years. replacement therapy. In part of his testimony he stated ‘I have Therefore, it would seem reasonable to believe that native no doubt that because of this treatment I’ve enjoyed five 3 Review article Bioscience Horizons • Volume 8 2015 years of quality life that I feared had passed me by’. This fibroblasts. Put simply, by expressing transcription factor powerful account shows the difference this treatment made (TF) genes for Oct4, Sox2, Klf4 and c-Myc cells obtained the to an individual who feels that others should be allowed to pluripotent characteristics of ESCs, these cells were termed experience the benefit of cell-based therapies. Two years later induced pluripotent stem cells (iPSCs). In the years following in July 2006 President George Bush vetoed the Stem Cell this study, similar techniques were used to produce iPSCs Research Enhancement Act of 2005, demonstrating that the from human cells. This offered an exciting new avenue for obstacles faced by stem cell research are also political and a stem cell research by circumventing the ethical dilemmas pre- greater public understanding is necessary for continuing viously associated with ESC research, while also providing advancements in this field. cells with an unhindered ability to differentiate down cell lin- eages. Animal studies that followed show that dopaminergic neurons derived from iPSCs improve motor symptoms in PD Induced pluripotent stem cells model rats (Wernig et al., 2008). As well as providing a potential source for transplantation, iPSCs derived from PD Although NSCs showed some promise they proved to be far patients could be paramount to modelling the disease in vitro from perfect, requiring invasive biopsies and only aiding in aiding the advance of drug therapies (Fig. 1). neuronal survival. In 2006, a research group in Japan led by Shinya Yamanaka (Takahashi and Yamanaka, 2006) devised As with adult stem cells, iPSCs eliminate the need for a method of deriving pluripotent cells from adult mouse immunosuppression by having a patient-derived cell source. Figure 1. Life cycle demonstrating the potential sources of induced pluripotent stem cells and the applications for cell replacement therapy or cellular modelling of Parkinson’s disease. [Reproduced from Brändl et al., (2014). © 2015 International Parkinson and Movement Disorder Society, with permission from John Wiley and Sons]. 4 Bioscience Horizons • Volume 8 2015 Review article Figure 2. (A) Image illustrating electrode implantation for deep brain stimulation. (B) Coronal section demonstrating the proximity of the implanted electrode to the intended target for cell replacement therapy highlighted in blue. [Reproduced from Rowland et al. (2014). © 2015 International Parkinson and Movement Disorder Society, with permission from John Wiley and Sons]. iPSCs also avoid the ethical issues associated with ESCs; Therefore, would it be correct to assume a cell replacement however, they do come with their own set of limitations. As therapy will be readily available in the foreseeable future? It is viral vectors are used to integrate the TF genes, they can also important that the current limiting factors of cell replacement randomly integrate elsewhere in the genome and modify cells therapy are taken into account. While studies have shown a further. These TF genes also have oncogenic potential as their reduction in motor symptoms, increased dopaminergic inner- increased expression could induce tumour formation, as was vation does not affect the non-motor symptoms of PD such as found in the PD model rats (Wernig et al., 2008). To over- fatigue, depression, hallucinations and mood swings. This is come this, it has been proposed that different methods be believed to be down to continued degeneration of serotoner- used to increase expression of these TFs other than introduc- gic projections to the brain regions controlling sleep, feeding ing DNA fragments (Yee, 2010). More recent studies have and emotion (Politis et al., 2012). Some evidence has also shown that mRNA can be implanted directly into cells with- emerged that the disease spreads from host cells to grafts, out genetic alteration; it is also possible to use DNA-based meaning transplants could eventually degenerate anyway vectors that are less likely to integrate into host genes (Brandl causing a recurrence of symptoms (Li et al., 2008). However, et al., 2014). It is apparent that with all of the discussed as PD is a late-onset slow- progressing degenerative disease, it potential cell therapies, there is need for further research into can be argued that grafts will last a patients’ lifetime or at their safety and efficacy to determine whether they could ever least provide relief for a significant portion. It can also be form the basis of a viable treatment for patients with PD. argued that while these grafts may not tackle the entire range of PD symptoms, grafts go a long way to relieving the most severe symptom, allowing patients to regain some level of What does this mean for cell function and an increased quality of life. replacement therapy? Studies have established that transplants survive and become Conclusion established within the striatum, improving dopaminergic delivery to the surrounding structures, aiding in fine motor In light of all the evidence discussed within this article, a cell- control and therefore abating the most debilitating symptom based treatment for PD has great potential and should be of PD. This has been demonstrated not only with improve- actively sought. Implants into animal models of PD and a ments in animal and human models but also with PET scan number of human grafts have proved to be effective in reduc- data showing Flurodopa uptake at graft sites. ing the cardinal motor symptoms of PD. It is necessary for 5 Review article Bioscience Horizons • Volume 8 2015 Brandl, B., Schneider, S. A., Loring, J. F. et al. (2014) Stem cell reprogram- larger clinical trials to take place to gain an appreciation for ming: basic implications and future perspective for movement dis- the effectiveness of cell-based therapies compared with the orders, Movement Disorders : Official Journal of the Movement current pharmacological gold standard. Patients undergoing Disorder Society, doi: 10.1002/mds.26113. surgery for DBS implantation would be a sensible population for a clinical trial. Individuals suitable for DBS already meet Clarke, D. L., Johansson, C. B., Wilbertz, J. et al. (2000) Generalized poten- a number of the criteria for biological studies. In addition, tial of adult neural stem cells, Science (New York, N.Y.), 288 (5471), these patients already require a surgical intervention and so it 1660–1663. would remove the need for sham surgical procedures, see Fig. 2 (Rowland et al., 2014). Knowledge gleamed from Congressional Record (2007) Volume 153, Part 6, Page 8582. US larger studies will make a valuable contribution to the field Government Printing Office, Washington. and encourage the development of cell therapies for other Dauer, W. and Przedborski, S. (2003) Parkinson’s disease: mechanisms neurodegenerative conditions. Although replacing dopami- and models, Neuron, 39 (6), 889–909. nergic neurons does not tackle the non-motor symptoms of PD, a stepwise approach to cell-based therapies is necessary. Dawson, T. M. and Dawson, V. L. (2003) Rare genetic mutations shed Future innovations may be able to provide a wider spectrum light on the pathogenesis of Parkinson disease, The Journal of of symptom relief. These implants alleviate the most debili- Clinical Investigation, 111 (2), 145–151. tating symptoms of PD and last long enough to significantly Defer, G. L., Geny, C., Ricolfi, F. et al. (1996) Long-term outcome of unilat- improve patient’s quality of life. With recent improvements in erally transplanted Parkinsonian patients. I. Clinical approach, Brain: both the safety profile and results demonstrated by cell-based A Journal of Neurology, 119 (Pt 1), 41–50. therapies, continued investment in future studies is justified. Ganz, J., Arie, I., Buch, S. et  al. (2014) Dopaminergic-like neurons Author’s biography derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model, PloS ONE, Tom is currently in his 5th year reading Medicine at Imperial 9 (6), e100445. College London. Last year he undertook a BSc in Neuroscience Hagell, P., Piccini, P., Bjorklund, A. et al. (2002) Dyskinesias following neu- and Mental Health to further his understanding of this fasci- ral transplantation in Parkinson’s disease, Nature Neuroscience, 5 (7), nating and rapidly evolving field of medicine. Following the 627–628. BSc, Tom is now strongly considering research as a future prospect alongside his clinical studies. Studying Neuroscience Hoffer, B. J., Leenders, K. L., Young, D. et al. (1992) Eighteen-month course has proved to further Tom’s interest; it stands out as a disci- of two patients with grafts of fetal dopamine neurons for severe pline of medicine he finds both challenging and thoroughly Parkinson’s disease, Experimental Neurology, 118 (3), 243–252. enjoyable. Tom endeavors to pursue his interest in this field Kim, J. H., Auerbach, J. M., Rodriguez-Gomez, J. A. et al. (2002) Dopamine over the coming years and hopes to attain an Academic neurons derived from embryonic stem cells function in an animal Foundation Programme job with a Neurology rotation, model of Parkinson’s disease, Nature, 418 (6893), 50–56. allowing him to partake in clinical medicine as well as devel- oping skills in research and teaching. Lévesque, M. F., Neuman, T. and Rezak, M. (2009) Therapeutic microin- jection of autologous adult human neural stem cells and differenti - References ated neurons for parkinson’s disease: five-year post-operative outcome, The Open Stem Cell Journal, 1, 20–29. Ambasudhan, R., Dolatabadi, N., Nutter, A. et al. (2014) Potential for cell Levivier, M., Dethy, S., Rodesch, F. et al. (1997) Intracerebral transplanta- therapy in Parkinson’s disease using genetically programmed tion of fetal ventral mesencephalon for patients with advanced human embryonic stem cell-derived neural progenitor cells, The Parkinson’s disease. 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Pharmacotherapy, 7 (10), 1399–1407. Ourednik, J., Ourednik, V., Lynch, W. P. et al. (2002) Neural stem cells dis- Takahashi, K. and Yamanaka, S. (2006) Induction of pluripotent stem play an inherent mechanism for rescuing dysfunctional neurons, cells from mouse embryonic and adult fibroblast cultures by defined Nature Biotechnology, 20 (11), 1103–1110. factors, Cell, 126 (4), 663–676. Parkinson, J. (1817) An Essay on The Shaking Palsy, Whittingham and The Guardian. Muhammad Ali and his battle. 20th March 2009 [Online], Rowland, London. accessed at: http://www.theguardian.com/lifeandstyle/2009/mar/20/ parkinsons-disease-muhammad-ali (24th October 2013). Peschanski, M., Defer, G., N’Guyen, J. P. et  al. (1994) Bilateral motor improvement and alteration of L-dopa effect in two patients with Tim Dahlberg. The Seattle Times. 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Cell replacement therapy in Parkinson's disease

Bioscience Horizons , Volume 8 – Mar 18, 2015

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BioscienceHorizons Volume 8 2015 10.1093/biohorizons/hzv002 Review article Tom Robert Barrow* Imperial College London, South Kensington, London SW7 2AZ, England *Corresponding author: 102 Rannoch Road, Hammersmith, London W6 9SW, England. Email: tom.barrow10@imperial.ac.uk Supervisor: Dr Jane L. Saffell, Imperial College London, South Kensington, London, SW7 2AZ, England. With an ageing population, the incidence of Parkinson’s disease is increasing. The disease has an overwhelming impact on those it affects and has a limited repertoire of drug therapies available, each with problematic side effects. Stem cell therapy is an exciting prospect in the treatment of several neurodegenerative conditions. This article takes an in depth look at the great potential of cell replacement therapy for Parkinson’s disease, providing supporting evidence for investment in this potential treatment. After considering the basis for cell replacement therapy, the article looks at stem cells of different origins, summing up the strengths and limitations of each in relation to Parkinson’s disease. In addition to highlighting the cell replace- ment therapies available, the article also provides a chronology of research into this emerging field over the last 30 years. Key words: Parkinson’s disease, stem cells, cell replacement therapy, stem cell transplant, regeneration, clinical trials Submitted on 24 August 2014; accepted on 16 February 2015 Introduction What is PD? In 1984, Muhammad Ali, the former heavyweight champion In 1817 James Parkinson documented six cases he had been of the world, was diagnosed with Parkinson’s disease (PD); observing in ‘An Essay on The Shaking Palsy’, describing the he began to experience tremors and a slowness in his move- classic motor symptoms of the disease that now bears his ments, known as bradykinesia. After years of battling with name and establishing it as a medical condition (Parkinson, the disease, Ali now has difficulty speaking and coordinating 1817). Today there is a greater understanding of the underly- his movements but remains an inspiration to many (The ing causes of these symptoms. However, what triggers degen- Guardian, 2009; Tim Dahlberg, The Seattle Times, 2012). eration of the dopaminergic neurons in the first place remains PD affects around 6.3 million people worldwide, with most unknown. Only 5% of PD cases can be attributed to specific diagnoses being made over the age of 60. It is currently an heritable genes such as PARK1, a gene responsible for encod- incurable disease associated with irreversible loss of the ing the neural protein α-synuclein (Dawson and Dawson, dopaminergic neurons in the substantia nigra (SN) and stria- 2003), the remaining 95% are idiopathic. Diagnosis of PD is tum, which are structures of the basal ganglia, essential for still a clinical diagnosis based on the four cardinal symptoms, fine motor control and initiation of movement ( Barker, as there is no definitive test. Symptoms become apparent once Cicchetti and Neal, 2012). As the central nervous system over 80% of the dopaminergic neurons have been lost (Miller (CNS) has a limited capacity to regenerate its neurons, this and O’Callaghan, 2014). On post-mortem examination, the has a devastating effect on motor function. Consequently, the SN of PD patients has a pale appearance. This is because four hallmark symptoms of PD are rigidity , tremor at rest, dopaminergic neurons are rich in neuromelanin, the substance bradykinesia and postural instability. Current drug therapies that gives rise to the dark pigmentation of the SN in normal target symptom management, and at present there are no adults (Zecca et al., 2003). Under a microscope abnormal cures for PD. This begs the question, is there potential for a aggregates of protein can be seen, known as Lewy bodies. treatment in the future and how does cell replacement ther- The specific cause of idiopathic PD is uncertain, it is likely to apy fit into the picture? be a combination of genetic and environment influences. © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.  Review article Bioscience Horizons • Volume 8 2015 For instance, MPTP exposure, a compound initially synthe- The idea of treating PD using cell replacement therapy is sized as a narcotic, induces symptoms of PD. This demon- not a new one; research in this area started in the early 1990s. strates the potential of environmental toxins having a role and Studies investigating the effects of foetal neuronal tissue in PD has provided one of the principal animal models of PD (Sian patients yielded promising results. A study published in 1994, et al., 1999). The two leading theories for the pathogenesis of transplanted foetal ventral mesencephalic tissue (which would PD centre around the aggregation of misfolded proteins (such later develop into the basal ganglia) rich in dopaminergic neu- as α-synuclein) and oxidative stress caused by mitochondrial roblasts (precursors) from aborted foetuses into the striatum dysfunction (Dauer and Przedborski, 2003). of two patients with idiopathic PD (Peschanski et al., 1994). The team followed up the patients and compared PET scan data of Flurodopa (dopamine with a radioactive isotope) with Current drug therapy motor changes. The results showed an increase in Flurodopa uptake at the site of grafting along with improved motor per- As PD is caused by a loss of the dopaminergic neurons, the formance in both patients. This study demonstrated that neu- main drug therapies focus on replenishing the dopamine ral transplantation was a possibility and was a step in the within the basal ganglia. By replacing the dopamine, motor right direction for cell replacement therapy; it showed that symptoms are reduced, and this has a significant impact on transplanted dopaminergic neurons could survive and re- patients’ quality of life. Dopamine precursors such as innervate the striatum. A number of studies reached the same Levodopa and dopamine agonists form the basis of current conclusions, adding strength to the potential of cell replace- therapy. Levodopa is augmented with a DOPA decarboxylase ment therapy as a treatment for PD (Hoffer et al., 1992; inhibitor to reduce peripheral conversion, ensuring the Defer et al., 1996; Levivier et al., 1997). majority of Levodopa is converted to dopamine within the CNS (Poewe and Antonini, 2014). Monoamine oxidase B These studies also demonstrated some of the limitations inhibitors can also be prescribed to reduce the breakdown of with transplantation of foetal tissue. One study retrospec- dopamine within the brain. While these drugs initially relieve tively followed up 14 patients who had received a graft of patients of their symptoms, their therapeutic benefit dimin - foetal mesencephalic tissue; the results showed that a number ishes with time. This is known as ‘wearing off’ and means of subjects suffered from graft-induced dyskinesias (Hagell patients require a higher dose to experience the same benefit et al., 2002). The mechanism behind this was not fully under- (Stocchi, 2006). Unfortunately, these drugs also have unpleas- stood, although it was hypothesized that the side effects ant side effects such as dyskinesia, which is the occurrence of could be due to dopamine reaching over-sensitized receptors involuntary movements. Although medication is the main- or due to the non-dopaminergic portions of the graft. It must stay of PD management, there are alternative treatments such also be appreciated that while these transplants demonstrated as speech and language therapy or surgical options such as the promising potential of cell replacement therapy, it is not a deep brain stimulation (DBS) (Odekerken et al., 2013). clinically viable model to use foetal tissue to treat PD patients. Current therapies have their limitations as they focus on It would be ethically questionable to use aborted foetal tissue symptomatic relief only and do nothing to reverse or slow as a treatment and require more than can be realistically down the progression of the disease. As PD is caused by sourced. degeneration of dopaminergic neurons, it stands to reason that differentiated stem cells could be implanted to replace Embryonic stem cells lost neurons and consequently re-innervate the striatum. Following the encouraging results of foetal tissue grafts, The case for cell replacement embryonic stem cells (ESCs) became the focus of research therapy into cell replacement therapy. Stem cells could provide the perfect source for neuronal replacement; ESCs are derived Cell replacement therapy is a promising avenue into the from the inner cell mass of the blastocyst and are pluripotent investigation and treatment of neurodegenerative diseases. with the ability to proliferate extensively. The CNS is unable to regenerate its own neurons, due to the physical and chemical barriers formed by glial scars (Ohtake A study looking at the effect of transplanting a low dose of and Li, 2014). Stem cells have the ability to multiply and dif- mouse ESCs to OHDA-lesioned (neurotoxic compound ferentiate down any cell line, this is known as pluripotency. which targets dopaminergic neurons) rats showed that the Current research is focussing on the pluripotent potential of naïve cells developed into functional dopaminergic neurons various forms of stem cells. By inducing stem cells to differ- in some cases (Bjorklund et al., 2002). Using PET scans and entiate under the correct conditions, dopaminergic neurons quantitative measurements of rotational behaviour in can be created. These neurons can be transplanted into a response to amphetamines, rats with ESC-derived dopami- patient with PD, replacing their dopamine levels and provid- nergic neurons showed some gradual but significant improve - ing symptomatic relief. Both the Michael J Fox Foundation ment of symptoms. However, this study also highlighted and Parkinson’s UK refer to stem cell therapies on their web- some unfavourable side effects. The study had a high rate of sites and actively back research into this potential therapy. tumour formation and graft failure. Of the 25 rats that 2 Bioscience Horizons • Volume 8 2015 Review article received the transplants, 6 showed no ESC survival and 5 neural stem cells, found in the subventricular zone and hip- died of teratoma-like tumours (Bjorklund et al., 2002). While pocampus, could be used in a similar way (Clarke et al., the study yielded some positive results, the high incidence of 2000). By implanting these neural stem cells (NSCs) into the tumour formation indicates some of the risks involved in striatum of PD patients, extracellular signalling might influ - transplanting highly proliferative tissues. ence their differentiation and form dopaminergic neurons. Another study published in Nature followed a similar A study conducted in 2002 implanted NSCs unilaterally procedure; here they looked at stimulating the differentia- into MPTP-treated mice (animal PD model). Following this, tion of ESCs into dopaminergic neurons in vitro before it was observed that some mice began rotating in the opposite transplanting these into an animal model of PD (Kim et al., direction to the implantation. An amphetamine challenge 2002). The results showed that the grafted ESC-derived neu- (causing DA release) and later histological evidence were rons survived and proved to be functional. However, the used to confirm that this was due to the implanted NSCs. study agreed that tumour formation was an unacceptable Although it was found that some of the transplanted cells complication associated with ESC grafts and that further differentiated into dopaminergic neurons, surprisingly it was animal studies were required to understand the safety and discovered that the majority of the dopaminergic neurons efficacy of these transplants. present were ‘rescued’ host cells (Ourednik et al., 2002). It was hypothesized that NSCs have an intrinsic ability to pro- Recent studies have since had mixed results in animal duce trophic (survival/growth) and neuroprotective factors models. However, improvements in culture methods and dif- sufficient to save damaged cells. The study demonstrated that ferentiation protocol have succeeded in creating a more NSCs migrated readily throughout the striatum, particularly homogenous and scalable population of dopaminergic neu- in the aged brain; here they were able to differentiate into rons (A9-type) specific to the ventrolateral and caudal regions dopaminergic neurons in response to host signals. In addi- of the SN. Animal models have subsequently seen improved tion, it showed the potential of NSCs to influence the existing outcomes, which correlates with evidence of increased fibre CNS, rescuing the present neurons and recovering the striatal outgrowth. Although, there is still concern as the potential dopaminergic system (Ourednik et al., 2002). for abherrant inervation and graft-induced dyskinesias remains unknown. It is hypothesized that genetic modifica - It is worth noting that adult stem cells can be derived from tion of these implanted neurons might be able to limit exces- sources other than the brain, which requires an invasive sive outgrowth (Ambasudhan et al., 2014). A number of biopsy. For instance, studies have demonstrated that stem techniques have been suggested to minimize the risk of cells can be harvested from the oral mucosa, endometrium, tumour formation; these include prolonged pre-differentia- bone marrow and adipose tissue. Given appropriate in vitro tion of ESCs, selection of differentiated cells for transplanta- signalling, these cells have the potential to differentiate into tion and genetic engineering to block tumourigenic pathways dopaminergic neurons and have also proven to be effective (Ambasudhan et al., 2014). when implanted into animal models of PD (Berg et al., 2014; Ganz et al., 2014; Wolff et al., 2015). The potential therapeutic use of ESCs and the possible complications are clearly demonstrated by these studies. As This demonstrates the promising advantages of adult stem with foetal tissue implants mentioned earlier, they hint cells compared with ESCs. Alongside showing similar regen- towards the intriguing potential for a method of regenerating erative potential in early trials, adult stem cells could be lost dopaminergic neurons in PD patients. Unfortunately, extensively cultured and potentially stimulated to differenti- they also demonstrate how far cell replacement therapy is ate in vitro. Another benefit of adult stem cells is that it does from being an operational procedure for PD patients. As with not depend on aborted foetal tissue, making it less ethically tissue implants, similar limitations apply. Both models require ambiguous, it also means there is a readily available self- immunosuppression to prevent graft rejection, and ESC derived source. It seems reasonable that with an appropriate transplants are associated with tumour formation. Supply of method, stem cells could be harvested, cultured, treated and ESCs is also limited and once again poses complicated ethical subsequently implanted into the striatum, overcoming the questions. issue of graft rejection. This potential therapy was carried out on Mr Dennis Adult stem cells Turner in the USA: after suffering from PD for 14 years and While ESCs provide promise for the future of PD treatment, experiencing severe symptoms, he received a transplant of his as a basis for cell replacement therapy the resources are lim- own NSCs that had been cultured and matured into dopami- ited. Interestingly, it has been discovered that adults also have nergic neurons from cortical tissues (Lévesque, Neuman and regions of undifferentiated, self-renewing stem cells. For Rezak, 2009). Mr Turner testified at a US Senate Committee instance, haematopoietic cells found in bone marrow are meeting in 2004 (Congressional Record, 2007) as an advo- precursors for all blood cell types in the body; these stem cate for the funding of research into treating PD using cell cells have been used successfully in transplants for years. replacement therapy. In part of his testimony he stated ‘I have Therefore, it would seem reasonable to believe that native no doubt that because of this treatment I’ve enjoyed five 3 Review article Bioscience Horizons • Volume 8 2015 years of quality life that I feared had passed me by’. This fibroblasts. Put simply, by expressing transcription factor powerful account shows the difference this treatment made (TF) genes for Oct4, Sox2, Klf4 and c-Myc cells obtained the to an individual who feels that others should be allowed to pluripotent characteristics of ESCs, these cells were termed experience the benefit of cell-based therapies. Two years later induced pluripotent stem cells (iPSCs). In the years following in July 2006 President George Bush vetoed the Stem Cell this study, similar techniques were used to produce iPSCs Research Enhancement Act of 2005, demonstrating that the from human cells. This offered an exciting new avenue for obstacles faced by stem cell research are also political and a stem cell research by circumventing the ethical dilemmas pre- greater public understanding is necessary for continuing viously associated with ESC research, while also providing advancements in this field. cells with an unhindered ability to differentiate down cell lin- eages. Animal studies that followed show that dopaminergic neurons derived from iPSCs improve motor symptoms in PD Induced pluripotent stem cells model rats (Wernig et al., 2008). As well as providing a potential source for transplantation, iPSCs derived from PD Although NSCs showed some promise they proved to be far patients could be paramount to modelling the disease in vitro from perfect, requiring invasive biopsies and only aiding in aiding the advance of drug therapies (Fig. 1). neuronal survival. In 2006, a research group in Japan led by Shinya Yamanaka (Takahashi and Yamanaka, 2006) devised As with adult stem cells, iPSCs eliminate the need for a method of deriving pluripotent cells from adult mouse immunosuppression by having a patient-derived cell source. Figure 1. Life cycle demonstrating the potential sources of induced pluripotent stem cells and the applications for cell replacement therapy or cellular modelling of Parkinson’s disease. [Reproduced from Brändl et al., (2014). © 2015 International Parkinson and Movement Disorder Society, with permission from John Wiley and Sons]. 4 Bioscience Horizons • Volume 8 2015 Review article Figure 2. (A) Image illustrating electrode implantation for deep brain stimulation. (B) Coronal section demonstrating the proximity of the implanted electrode to the intended target for cell replacement therapy highlighted in blue. [Reproduced from Rowland et al. (2014). © 2015 International Parkinson and Movement Disorder Society, with permission from John Wiley and Sons]. iPSCs also avoid the ethical issues associated with ESCs; Therefore, would it be correct to assume a cell replacement however, they do come with their own set of limitations. As therapy will be readily available in the foreseeable future? It is viral vectors are used to integrate the TF genes, they can also important that the current limiting factors of cell replacement randomly integrate elsewhere in the genome and modify cells therapy are taken into account. While studies have shown a further. These TF genes also have oncogenic potential as their reduction in motor symptoms, increased dopaminergic inner- increased expression could induce tumour formation, as was vation does not affect the non-motor symptoms of PD such as found in the PD model rats (Wernig et al., 2008). To over- fatigue, depression, hallucinations and mood swings. This is come this, it has been proposed that different methods be believed to be down to continued degeneration of serotoner- used to increase expression of these TFs other than introduc- gic projections to the brain regions controlling sleep, feeding ing DNA fragments (Yee, 2010). More recent studies have and emotion (Politis et al., 2012). Some evidence has also shown that mRNA can be implanted directly into cells with- emerged that the disease spreads from host cells to grafts, out genetic alteration; it is also possible to use DNA-based meaning transplants could eventually degenerate anyway vectors that are less likely to integrate into host genes (Brandl causing a recurrence of symptoms (Li et al., 2008). However, et al., 2014). It is apparent that with all of the discussed as PD is a late-onset slow- progressing degenerative disease, it potential cell therapies, there is need for further research into can be argued that grafts will last a patients’ lifetime or at their safety and efficacy to determine whether they could ever least provide relief for a significant portion. It can also be form the basis of a viable treatment for patients with PD. argued that while these grafts may not tackle the entire range of PD symptoms, grafts go a long way to relieving the most severe symptom, allowing patients to regain some level of What does this mean for cell function and an increased quality of life. replacement therapy? Studies have established that transplants survive and become Conclusion established within the striatum, improving dopaminergic delivery to the surrounding structures, aiding in fine motor In light of all the evidence discussed within this article, a cell- control and therefore abating the most debilitating symptom based treatment for PD has great potential and should be of PD. This has been demonstrated not only with improve- actively sought. Implants into animal models of PD and a ments in animal and human models but also with PET scan number of human grafts have proved to be effective in reduc- data showing Flurodopa uptake at graft sites. ing the cardinal motor symptoms of PD. It is necessary for 5 Review article Bioscience Horizons • Volume 8 2015 Brandl, B., Schneider, S. A., Loring, J. F. et al. (2014) Stem cell reprogram- larger clinical trials to take place to gain an appreciation for ming: basic implications and future perspective for movement dis- the effectiveness of cell-based therapies compared with the orders, Movement Disorders : Official Journal of the Movement current pharmacological gold standard. Patients undergoing Disorder Society, doi: 10.1002/mds.26113. surgery for DBS implantation would be a sensible population for a clinical trial. Individuals suitable for DBS already meet Clarke, D. L., Johansson, C. B., Wilbertz, J. et al. (2000) Generalized poten- a number of the criteria for biological studies. In addition, tial of adult neural stem cells, Science (New York, N.Y.), 288 (5471), these patients already require a surgical intervention and so it 1660–1663. would remove the need for sham surgical procedures, see Fig. 2 (Rowland et al., 2014). Knowledge gleamed from Congressional Record (2007) Volume 153, Part 6, Page 8582. US larger studies will make a valuable contribution to the field Government Printing Office, Washington. and encourage the development of cell therapies for other Dauer, W. and Przedborski, S. (2003) Parkinson’s disease: mechanisms neurodegenerative conditions. Although replacing dopami- and models, Neuron, 39 (6), 889–909. nergic neurons does not tackle the non-motor symptoms of PD, a stepwise approach to cell-based therapies is necessary. Dawson, T. M. and Dawson, V. L. (2003) Rare genetic mutations shed Future innovations may be able to provide a wider spectrum light on the pathogenesis of Parkinson disease, The Journal of of symptom relief. These implants alleviate the most debili- Clinical Investigation, 111 (2), 145–151. tating symptoms of PD and last long enough to significantly Defer, G. L., Geny, C., Ricolfi, F. et al. (1996) Long-term outcome of unilat- improve patient’s quality of life. With recent improvements in erally transplanted Parkinsonian patients. I. Clinical approach, Brain: both the safety profile and results demonstrated by cell-based A Journal of Neurology, 119 (Pt 1), 41–50. therapies, continued investment in future studies is justified. Ganz, J., Arie, I., Buch, S. et  al. (2014) Dopaminergic-like neurons Author’s biography derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model, PloS ONE, Tom is currently in his 5th year reading Medicine at Imperial 9 (6), e100445. College London. Last year he undertook a BSc in Neuroscience Hagell, P., Piccini, P., Bjorklund, A. et al. (2002) Dyskinesias following neu- and Mental Health to further his understanding of this fasci- ral transplantation in Parkinson’s disease, Nature Neuroscience, 5 (7), nating and rapidly evolving field of medicine. Following the 627–628. BSc, Tom is now strongly considering research as a future prospect alongside his clinical studies. Studying Neuroscience Hoffer, B. J., Leenders, K. L., Young, D. et al. (1992) Eighteen-month course has proved to further Tom’s interest; it stands out as a disci- of two patients with grafts of fetal dopamine neurons for severe pline of medicine he finds both challenging and thoroughly Parkinson’s disease, Experimental Neurology, 118 (3), 243–252. enjoyable. Tom endeavors to pursue his interest in this field Kim, J. H., Auerbach, J. M., Rodriguez-Gomez, J. A. et al. (2002) Dopamine over the coming years and hopes to attain an Academic neurons derived from embryonic stem cells function in an animal Foundation Programme job with a Neurology rotation, model of Parkinson’s disease, Nature, 418 (6893), 50–56. allowing him to partake in clinical medicine as well as devel- oping skills in research and teaching. Lévesque, M. F., Neuman, T. and Rezak, M. (2009) Therapeutic microin- jection of autologous adult human neural stem cells and differenti - References ated neurons for parkinson’s disease: five-year post-operative outcome, The Open Stem Cell Journal, 1, 20–29. Ambasudhan, R., Dolatabadi, N., Nutter, A. et al. (2014) Potential for cell Levivier, M., Dethy, S., Rodesch, F. et al. (1997) Intracerebral transplanta- therapy in Parkinson’s disease using genetically programmed tion of fetal ventral mesencephalon for patients with advanced human embryonic stem cell-derived neural progenitor cells, The Parkinson’s disease. 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