parkinson 's disease ( pd ) is a neurodegenerative condition characterised clinically as a movement disorder consisting of bradykinesia , rigidity and rest tremor , as a consequence of striatal dopamine depletion secondary to degeneration of the dopaminergic neurons of the substantia nigra .
in addition , pathology in other regions results in cognitive deficits and a dementia in some cases , neuropsychiatric manifestations including depression and anxiety , sleep disturbances including rapid - eye movement sleep behavior disorder , and autonomic features ( kalia and lang , 2015 ) .
the motor disorder of pd responds well to dopamine - replacement therapies such as levodopa or dopamine agonists . however , systemic administration of dopaminergic agents results in non - physiological release of dopamine in the striatum resulting over time in disabling motor dyskinesias , and off - target effects resulting in neuropsychiatric complications , including impulse control behaviours , which can be very severe in some patients .
there remains therefore , a currently unmet need for a means of introducing dopamine to the striatum in a more physiological and targeted manner , and as such there is much interest in emerging cell - based regenerative treatments for pd ( jenner , 2003 ; barker et al .
, 2015 ; kalia and lang , 2015 ) . a variety of sources of dopaminergic cells have been investigated for treating pd in this way , and in this review we discuss the basis of these , as well as their prospects for use in clinical practice .
dopaminergic neurons can be obtained from several sources to serve as the basis for potential cell - based therapies .
any neural tissue grafted must have the ability to produce dopamine , demonstrate axonal outgrowth , and form connections with the host striatum , without widespread migration of grafted cells or malignant transformation .
fetal ventral mesencephalon ( fvm ) tissue contains progenitors for dopamine - producing neurons , and has been transplanted into the striatum of pd patients with good results in a number of patients ( kefalopoulou et al . , 2014 ; barker et al . ,
clinical efficacy and safety has been highly variable in trials of human fvm grafting , partly due to suboptimal patient selection , grafting technique , immunosuppressive regimes and trial design ( freed et al . , 2001 ;
however , in appropriately selected patients ( using criteria including age less than 65 years and minimal pre - existing dyskinesia ) , this strategy seems to be effective and at the very least has shown an important proof - of - concept that dopaminergic neuron replacement for pd is a therapeutic option ( barker et al . , 2015 ) .
although fetal dopaminergic cells have shown an important proof - of - principle , there are major logistical and ethical problems linked to their use which has led to the search for a better source of cells for grafting in pd .
the generation of induced pluripotent stem cells ( ipscs ) through forced expression of pluripotency factors in adult human somatic cells led to much interest in these as a potential cell - based treatment for pd ( takahashi et al . , 2007 ) .
nigral dopaminergic neurons can be generated from ipscs by exposure to specific factors that induce neuronal differentiation and midbrain patterning ( soldner et al .
this approach potentially would mean that a patient - specific therapy could be generated for each individual ( autologous grafting ) , circumventing the need for the immunosuppression that is required when using allografts .
comparison of the major approaches to cell - based therapies in parkinson 's disease an alternative approach to the use of ipsc - derived neurons is to generate dopaminergic neurons from embryonic stem ( es ) cells which could be used for allogeneic grafting ( thomson et al . , 1998 ) .
like ipscs , these can be differentiated into neurons and directed to a midbrain lineage to produce authentic a9 dopaminergic neurons ( kriks et al . , 2011 ) .
it has recently emerged that the markers that have been traditionally used to signify nigral dopaminergic neuronal fate fail to predict positive graft outcomes .
this has now been achieved showing that midbrain patterning alone is not sufficient to produce high numbers of dopaminergic neurons , but rather neural progenitors must be specifically patterned to the caudal midbrain in order to achieve high yields of nigral dopaminergic neurons ( kirkeby et al . , 2017 ) .
this finding reiterates the importance of protocol optimization prior to commencement of clinical trials of cell - based therapies that involve cellular reprogramming .
a more recent development has been the direct conversion of adult somatic cells into induced neurons ( ins ) using viral vectors to transfer proneural transcription factors , bypassing the stem cell intermediate stage ( vierbuchen et al . ,
this approach could theoretically be used to generate patient - specific dopaminergic neuronal autografts , and human ins have been shown to survive transplantation into rodents , and maintain their phenotype ( pereira et al . , 2014 ) .
however , the lack of highly efficient , consistent protocols for deriving functional dopamine - producing ins at the present time means that their utility is likely to be limited to in vitro disease - modelling , at least for the foreseeable future .
in order for any of the above approaches to be adopted in a clinical setting , they need to not only be effective and capable of restoring striatal dopaminergic tone , but also commercially viable and ethically acceptable .
furthermore , any cell - based therapy must be able to compete with current treatments such as pharmacological dopamine replacement and deep brain stimulation , and also emerging pharmaceutical treatments .
as work towards disease - modifying therapies progresses , it may be that the optimal treatment approach involves a combination of pharmacological agents ( e.g. , neurotrophic factors or antioxidants ) or immunotherapies targeting alpha - synuclein to limit disease progression , and cell - based therapies to restore the dopaminergic motor function that has already been lost .
clinical trials investigating these approaches must be initiated only on the basis of sound pre - clinical data , with flawed , premature trials likely to be detrimental to the whole field , especially in the case of cell - based therapies .
furthermore , these treatments must be targeted to the population of patients that are most likely to benefit from them .
there is clearly heterogeneity within the pd spectrum , with some patients experiencing a predominantly motor disorder , and others at increased risk of early cognitive impairment and dementia ( williams - gray et al . , 2007 ) .
it is the former group that is likely to derive the most benefit from dopamine cell - based treatments , which do not target the cortical and subcortical cholinergic pathology , which is presumably more prominent in the latter group . in view of the discordance seen between the promising early trials of human fvm grafting and the two negative randomized - controlled trials ,
further investigation is necessary to determine which factors are critical for successful transplant outcomes ( freed et al . , 2001
; olanow et al . , 2003 ) . an ongoing clinical trial for human fvm grafting ( transeuro ) , in which refined patient selection and an optimized grafting and immunosuppression protocol has been adopted ( based on an analysis of all available data from prior trials ) ,
is expected to be published in 2020 . in this trial , at least 3 fvms are grafted per side , with tissue being sited stereotactically via five to seven tracts into the posterior putamen .
patients receive 12 months of standard triple agent immunotherapy , in the form of cyclosporine a , azathioprine and prednisolone  an approach that bears a close resemblance to the early trials undertaken in sweden in the late 1980s/1990s .
one of these patients grafted with human fvm during these early trials in sweden has recently come to post - mortem .
histological analysis demonstrated survival of the graft , albeit with some intragraft lewy body pathology , 24 years post - transplantation ( li et al . , 2016 ) .
whilst fvm grafts are clearly effective in a population of pd patients , the ethical considerations surrounding the use of fetal tissue , and the logistical challenge of accessing adequate tissue ( at least three fetal midbrains are required per grafted side of brain ) means that this approach will not be suitable for widespread clinical use . nevertheless ,
if the transeuro trial demonstrates clinical benefit , this will serve as an important stepping - stone for clinical trials using stem cell products .
the important remaining question will then be whether to pursue autologous ipsc - derived grafts or allogeneic ipsc or es cell - derived grafts ( barker et al . , 2015 ) .
ipscs are a means of generating patient - specific autologous grafts , theoretically meaning that they have a low risk of rejection , circumventing the need for immunosuppression .
this is often cited as the major advantage of this approach over the use of allogeneic tissue , such as grafts derived from es cells ( barker et al . , 2015 ; stoker and barker , 2016 ) .
however , generation of patient - specific grafts from ipscs on a large scale for use in healthcare brings about significant technical , regulatory and financial challenges .
variability in the response of each individual cell line to differentiation protocols means that the product will differ between patients , meaning that each graft generated will necessarily be subject to regulatory approval , and the associated costs .
additionally , it may not be possible to generate specific target cell types for every pluripotent cell line without time - consuming and expensive optimisation of the differentiation protocol for that particular cell line .
the cost of generating autologous grafts via ipscs is therefore likely to be prohibitively high , meaning that this approach is unlikely to be practicable for treatment of common diseases for the foreseeable future ( table 1 ) .
one potential avenue to reduce the regulatory and economic barriers to the use of ipsc - derived autografts , is the development of haplobanks consisting of graft products derived from a relatively small number of individuals with specific hla types , allowing hla - matched grafts to be available for the majority of the population .
it has been estimated that hla - matched grafts could be generated for almost 95% of the uk population by obtaining cell lines from 150 individuals ( taylor et al . , 2012 ) .
this is an appealing prospect , but in order to keep the required number of donor cell lines to relatively low levels , mismatch of up to two hla loci must be accepted . in this circumstance , a period of immunosuppression may therefore still be necessary , nullifying the main advantage of ipsc - derived grafts over allogeneic grafts . indeed , as the intended site of these grafts ( the central nervous system ) is a relatively immunologically privileged site , long courses of immunosuppression are unlikely to be necessary , regardless of whether grafts are autologous or allogeneic .
six to twelve months of standard immunotherapy has been employed in fvm grafts to date , which seems sufficient to prevent graft rejection ( barker et al . , 2015 )
 supported by the survival of the aforementioned fvm graft at 24 years ( though it must be noted that this patient had received 64 months of immunosuppression ) ( li et al . , 2016 ) .
similarly , ins are unlikely to offer a commercially viable alternative even if efficient protocols for producing functional dopaminergic neurons are developed .
in addition to the above challenges , another disadvantage of autologous grafts is the fact that , given that pd pathogenesis is increasingly understood to involve several genetic susceptibility factors , they will retain the individual 's inherent propensity to develop recurrent pd pathology .
taking these considerations into account , es cells currently present the most promising approach for a commercially viable cell - based treatment for pd , especially also given some concerns over the stability of ipsc reprogramming .
although a period of immunosuppression will be necessary with this approach , this is an acceptable cost to allow development of a product that is both clinically effective and commercially viable .
furthermore , as mentioned above , this course of immunosuppression is likely to be limited to a period of months , restricting the burden of adverse effects .
the ability to generate a standardized product from the most efficient es cell line means that neurons can be cryogenically stored , avoiding the need to navigate the regulatory environment for each individual , as would be the case with autologous grafts ( table 1 ) .
clinical trials of es cell - derived grafts will be commencing in the next few years , with the american nystem trial due to commence in 2018/2019 , and the stem - pd trial in the united kingdom and sweden likely to begin in 2019/2020 .
of course , ethical objections to the use of embryonic tissue will remain a potential barrier to use in some circumstances , but taking into account logistical and economic factors , es cell - derived treatments appear to be the most likely to fulfil the criteria for widespread clinical use .
development of cell - based treatments for pd has been a long process , with progress being iterative . prematurely conducted trials in the past
have cast doubt over this approach , but robustly designed studies are currently ongoing or are planned , to determine whether these treatments can offer a clinically useful therapy .
human fvm grafting has served as a stepping stone to stem cell - based treatments , offering important proof - of - concept data .
the significant economic and logistical challenges of using autologous tissue relating to variation in the original cell sample , response to differentiation protocol , and the final product , means that es cells probably offer the greatest hope of a useful therapeutic approach , at least in the short to medium term .
clinical trials in pd of midbrain dopaminergic neurons derived from es cells ( usa , united kingdom / sweden ) and from ipscs ( japan / usa ) are planned to commence in the next few years , the results of these will be crucial in determining the future direction for the field of regenerative medicine in pd .
 parkinson 's disease ( pd ) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra . 
 the motor disorder responds well to dopamine - replacement therapies , though these result in significant adverse effects due to non - physiological release of dopamine in the striatum , and off - target effects . 
 cell - based regenerative treatments offer a potential means for targeted replacement of dopamine , in a physiological manner . 
 dopaminergic neurons for cell - based therapies can be obtained from several sources . 
 fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors , and has been transplanted into the striatum of pd patients with good results in a number of cases . 
 however , the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting . 
 induced pluripotent stem cells can be used to generate dopaminergic neurons for transplantation , providing a source of autologous tissue for grafting . 
 this approach means that challenges associated with allografts , such as the potential for immune rejection , can be circumvented . 
 however , the associated cost and difficulty in producing a standardized product from different cell lines means that , at present , this approach is not commercially viable as a cell - based therapy . 
 dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell - based therapy for parkinson 's disease , with trials due to commence in the next few years . 
 though there are ethical considerations to take into account when using embryonic tissue , the possibility of producing a standardized , optimized cell product means that this approach can be both effective , and commercially viable . 
Introduction
Strategies for Cell-Based Therapies in PD
Prospects for the Clinic
Conclusions