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Send Orders for Reprints to [email protected] Current Gene Therapy, 2018, 18, 206-224

REVIEW ARTICLE ISSN: 1566-5232 eISSN: 1875-5631

Cellular, Molecular and Non-pharmacological Therapeutic Advances for the Treatment of Parkinson's Disease: Separating Hope from Hype

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BENTHAM SCIENCE

Mehdi Ghamgosha1, Ali Mohammad Latifi1, Gholam Hossein Meftahi2 and Alireza Mohammadi2,* 1

Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 2Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

ARTICLE HISTORY Received: April 10, 2018 Revised: August 24, 2018 Accepted: September 05, 2018 DOI: 10.2174/1566523218666180910163401

Abstract: Parkinson’s Disease (PD) is a frustrating condition characterized by motor and nonmotor deficits majorly caused by the loss of dopaminergic cells in the Substantia Nigra pars compacta (SNc) and destruction of the nigrostriatal pathway. Despite the very respectable advances in cutting-edge approaches for the treatment of PD, there exist numerous challenges that have incapacitated the definitive treatment of this disease. This review emphasized the development of various non-pharmaceutical therapeutic approaches and mainly highlighted the cutting-edge treatments for PD including gene- and stem cell-based therapies, targeted delivery of neurotrophic factors, and brain stimulation techniques such as Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), and Deep Brain Stimulation (DBS). The review covered various gene therapy strategies including Adeno-Associated Virus-Glutamic Acid Decarboxylase (AAV-GAD), AAV–Aromatic L-Amino Acid Decarboxylase (AAV-AADC), Lenti-AADC/Tyrosine Hydroxylase/Guanosine TriphosphateCyclohydrolase I (Lenti-AADC/TH/GTP-CH1), AAV–Neurturin (AAV-NRTN), α -Synuclein silencing, and PRKN gene delivery. Also, the advantages, disadvantages, and the results of trials of these methods were discussed. Finally, reasons for the failure of PD treatment were described, with the hopes separated from hypes.

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Keywords: PRKN gene delivery, α-Synuclein silencing, tDCS, DBS, Cell therapy, AAV-GAD. 1. INTRODUCTION

PD is a frustrating condition characterized by motor and nonmotor deficits majorly caused by the loss of dopaminergic cells in the SNc and destruction of the nigrostriatal pathway [1, 2]. The nigrostriatal pathway links the SNc with the dorsal striatum (the putamen and caudate nucleus), and the devastation of neurons in this pathway lead to cardinal symptoms of PD, including tremor, rigidity, postural instability, and akinesia. Though brain imaging and electroencephalographic studies are applied in the early diagnosis of neurological disorders [3, 4], PD symptoms become evident when about 60% of dopaminergic neurons have been destroyed [1]. Although the exact cellular and molecular mechanisms leading to the degeneration of dopaminergic cells in PD are unclear, the identification of several mutations in SNCA (PARK1 or PARK4), PRKN (PARK2 or parkin RBR E3 ubiquitin protein ligase), GAK (cyclin G-associated kinase), GBA (β-glucocerebrosidase), LRRK2 (Leucine-rich repeat kinase 2 or PARK8), DJ-1 (PARK7), PARK16, NAT2 (Nacetyltransferase 2), PINK1 (PTEN-induced putative kinase 1 or PARK6), HLA-DRA and ATP13A2 (PARK9) genes *Address correspondence to this author at the Neuroscience Research Center, Baqiyatallah University of Medical Sciences, P.O. Box: 19395-6558, Postal Code: 1413643561, Tehran, Iran; Tel: +98 (21) 26127286; E-mail: [email protected] 1875-5631/18 $58.00+.00

have made an inimitable glance into the mechanisms responsible for the etiology of PD [5-10]. The SNCA gene is recognized as the main causative gene responsible for producing a protein with 140 amino acids, α -synuclein (α-syn). It has been previously stated that α-syn may be a chief element of Lewy Bodies (LBs), a well-known neuropathological biomarker of PD. LBs are usually diffused through the substantia nigra, hypothalamus, locus ceruleus, and cerebral cortex [11]. Several studies have shown that mitochondrial dysfunction may occur due to loss of function of PRKN, PINK1, LRRK2, and DJ-1 [12-16]. Moreover, it has been revealed that mitochondrial dysfunction, lysosomal degradation, overproduction of Reactive Oxygen Species (ROS), reduced antioxidant molecules (e.g., DJ-1) and oxidatively modified dopamine (DA-Ox) accelerate the accumulation of α-syn in the oligomers, fibrils and eventually LBs (Fig. 1) [17, 18]. Current pharmacological therapies for PD (levodopa, Catechol-O-Methyltransferase (COMT) inhibitors, dopamine receptor agonists, and monoamine oxidase B inhibitors) led to increased activity of the remaining dopaminergic neurons. The useful effects of levodopa as the gold standard of these drugs decrease by way of the remaining dopaminergic cells losing their ability over time [19]. Therefore, effective treatment for PD has mostly failed because of these limitations and the late diagnosis of the disease. In this review, the de-

© 2018 Bentham Science Publishers

Therapeutic Advances in the Treatment of PD

Current Gene Therapy, 2018, Vol. 18, No. 4

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Fig. (1). The pathophysiological mechanisms of Lewy body formation in PD. Loss-of-function or mutations in PRKN, PINK1, and DJ-1 due to mitochondrial dysfunction and induction of autophagy. LRRK2 is involved in chaperone-mediated autophagy and phosphorylation of Microtubuleassociated Protein Tau (MAPT) and α -syn. The ubiquitin-proteasome system eliminates misfolded and damaged proteins from the cytosol, endoplasmic reticulum, and nucleus. Auto-oxidation of dopamine (Ox-DA), lysosomal degradation, Reactive Oxygen Species (ROS) overproduction, and decreased redox-sensitive chaperone molecules like DJ-1, accelerates the accumulation of α-syn in the oligomers, fibrils, and eventually LBs. Aβ and tau considerably induce the assembly of α-syn into fibrils.

velopment of various non-pharmaceutical therapeutic approaches will be emphasized and the cutting-edge treatments for PD including gene- and stem cell-based therapies, targeted delivery of neurotrophic factors, and brain stimulation techniques such as transcranial direct current stimulation (tDCS), Transcranial Magnetic Stimulation (TMS), and Deep Brain Stimulators (DBS) highlighted. Also, the advantages and disadvantages of these methods will be discussed, and the hopes separated from hypes. 2. GENE THERAPY

Gene therapy for PD has obvious potential benefits as it can increase the accessibility of dopamine synthesis precursors and can be used to retain and/or repair dopaminergic neurons as well [20-23]. Gene therapy can correct a specific genetic defect by increasing, decreasing or silencing the expression of target genes, or induction of endogenous production of a therapeutic protein. Transferring genes encoding therapeutic proteins to targeted regions of the brain like SNc or striatum may be a hopeful moment for the improvement of motor and non-motor complications of PD. It has been illustrated that the loss of dopaminergic cells is delayed by neurturin (NRTN) or Glial cell line-derived Neurotrophic

Factor (GDNF) recombinant proteins delivery to the SNc or striatum [20, 24-29]. On the other hand, the polarity and large size of these proteins lead to protein misfolding and consequently their inactivity. Other disadvantages include the inability to easily cross the Blood-Brain Barrier (BBB) and, in some cases, significant side effects that reduce their therapeutic value [30-33]. Therefore, the peripherally administered vectors are not able to cross the BBB and necessitate direct injecting into the brain. Although gene therapy has some shortcomings and disadvantages, the improvements indicate its ability to improve dopaminergic cells and help to resolve motor and non-motor problems in Parkinson’s. Hence, gene delivery may be an efficient approach to convey trophic factors to the SNc or striatum of patients with PD. 2.1. Viral Vectors Recombinant viruses as the most proficient vehicles to realize long-term constant gene expression has been extensively utilized as vectors for the production of therapeutic proteins. The most commonly used vectors for gene delivery to the brain are based on lentivirus (for example HIV-1), herpes simplex virus (like type 1 or HSV-1), adenovirus,

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Adeno-Associated Virus (AAV), retrovirus, SV40, equine infectious anemia virus, and feline immunodeficiency virus. AAV and lentivirus vectors are used as the non- or low-toxic eminent vectors for gene delivery to the brain [34-38], however, it has been shown that AAV vectors are capable of exciting T lymphocyte cytotoxic response [39].

[51, 57]. These findings were completed in 13 adult MPTPinduced hemiparkinsonian rhesus monkeys, as [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) investigation showed that the STN AAV-GAD treatment resulted in an increased glucose metabolism of motor cortex and significant clinical rating improvement [50]. Furthermore, behavioural but not neuroprotective eﬀect of STN AAV-GAD65 treatment have been replicated in a 6-OHDAlesioned rat model of PD [42, 57]. In contrast, AAV genomes were detected in STN but not in the blood or any other tissues of STN rAAV2-GAD-treated rat model of PD [42]. The first clinical trial AAV–GAD gene therapy in patients with PD was conducted in an open-label nonrandomized phase I trial which dates back to 2007. Kaplitt and colleagues injected unilateral STN AAV2-GAD65/67 into 12 (11 men and 1 woman) PD patients and noteworthy improvements were observed 3 to 12 months post-surgery in the motor Unified Parkinson’s Disease Rating Scale (UPDRS) scores. From their findings, AAV2-GAD65/67 gene therapy of the STN was harmless and well tolerated by patients with advanced PD [58]. Subsequently, Feigin and coworkers (2007) confirmed these findings using FDG-PET and stated that unilateral STN AAV-GAD gene therapy leads to a reduction of metabolism in the pallidum and thalamus of the operated side [59]. It has also been revealed that the improved motor UPDRS scores are associated with increases in the premotor cortex metabolism of the same hemispheres [60]. A randomized, double-blind, phase II trial of bilateral STN AAV2-GAD65/67 in 45 patients with progressive levodopa-responsive PD, with significantly low motor UPDRS scores, were compared with controls. The results of 6 months monitoring revealed a considerable improvement of STN AAV2-GAD group in motor UPDRS scores than that of the controls. The safety and efficacy of STN AAV2GAD were listed as the strengths of this study, and nausea, headache, and a bowel obstruction as its side effects; however, it was stated that the last case was not attributed to the intervention or surgical procedure [56]. In a newly reported bilateral STN AAV2-GAD randomized and double-blind study, 45 PD patients were followed for 12 months by motor UPDRS scores and FDG-PET imaging. The results showed a significant decrease in daily dyskinesias duration in STN AAV2-GAD group than that of the controls. Significant metabolic decreases in the striatum, thalamus, orbitofrontal, anterior cingulate, and prefrontal cortices were reported in the STN AAV2-GAD group compared with the sham group [61]. Although studies have emphasized the effectiveness of STN AAV2-GAD, it has been revealed that the mean level of improvement in the Deep Brain Stimulation (DBS) of the STN (STN DBS) was more than that observed with STN AAV2-GAD gene therapy [62].


The recombinant AAA Vector (rAAV) is derived from the non-pathogenic parvoviruses facilitating proficient gene transfer into dividing and non-dividing cells in various organelles including the brains. Hadaczek and colleagues (2010) showed that AAV2-hAADC-mediated transgene expression continued for at least 8 years with no signs of neuroinflammation or reactive gliosis in a monkey’s brain [40]. Among AAVs 1–10, AAV-2-derived vectors are the most commonly used serotype in PD gene delivery, because a high percentage of gene expression is limited to the injected or manipulated regions such as SNc, and Subthalamic Nucleus (STN) [41, 42]. Dodiya and coworkers (2010) reported that AAV2/1 and AAV2/5 are superior to AAV2/8 for gene delivery to striatum of the nonhuman primate [43]. Moreover, it has been previously reported that the proficiency of AAV2/1, AAV2/5 is similar to or superior to that of AAV2/8 in the striatum [44-47]. While many vectors including the AAV have immune responses and cannot be reused if they fail, some of these disadvantages can overcome using hybrid vectors [48, 49].

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2.2. The Most Important Gene Therapy Approaches in PD

Currently, there are six most important gene therapy approaches for the treatment or improvement of the main motor signs of PD. Surprisingly, all of these gene therapy strategies have been developed based on AAV or lentivirus vectors. They consist of AAV-GAD, AAV-AADC, LentiAADC/TH/GTP-CH1, AAV-NRTN, α-Synuclein silencing, and PRKN gene delivery. AAV-GAD, AAV-AADC, and Lenti-AADC/TH/GTP-CH1 strategies improve motor signs via conveying neurotransmitter-producing enzyme and the remaining is based on gene delivery or disease-modifying approaches [50-53]. Development of the various gene therapy approaches is summarized in Fig. (2). 2.2.1. AAV-Glutamic Acid Decarboxylase (AAV-GAD)

PD is associated with a decrease in gamma-aminobutyric acid (GABA)ergic inputs into the STN and leads to its hyperactivity [54, 55]. Glutamic Acid Decarboxylase (GAD) is a central enzyme with two isoforms GAD65 and GAD67 and plays a key role in the production of GABA in the brain. GABA as the crucial inhibitory neurotransmitter of the Central Nervous System (CNS) compensates for the lost inhibitory mechanism in the basal ganglia via reducing neuronal excitability. Hence, transfer of the gene encoding GAD into the STN (STN AAV-GAD) or other basal ganglia nuclei could upsurge GABA synthesis and subsequently leads to an equilibrium of these pathways [50, 55, 56]. It has been shown that transfer of GAD-encoding gene into glutamatergic neurons of the STN using an AAV vector, leads to release of GABA in an activity-dependent manner in 6-hydroxydopamine (6-OHDA)-lesioned rats and consequently improve firing rates regulation and motor deficits

2.2.2. AAV–Aromatic L-Amino Acid Decarboxylase (AAV– AADC) Aromatic L-Amino Acid Decarboxylase (AADC) or DOPA decarboxylase is defined as a lyase enzyme that transforms pharmacologic or endogenous levodopa to dopamine, L-tryptophan to tryptamine, and 5-Hydroxytryptophan (5HTP) to serotonin. It has been suggested that the gradual death of dopaminergic neurons is associated with reduced


PRKN gene delivery

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Neuroprotective effect

Harmful potential

Insignificant improvement of the UPDRS score

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Lenti-AADC/TH/GTP-CH1

Minor improvements

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Significant reduced dyskinesia


AAV-GAD

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Phase I

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Fig. (2). Development of the various gene therapy approaches in PD. AAV-GAD: AAV-Glutamic Acid Decarboxylase, AAV-AADC: AAV–Aromatic L-Amino Acid Decarboxylase, Lenti-AADC/TH/GTP-CH1, Lenti-AADC/Tyrosine Hydroxylase/Guanosine Triphosphatecyclohydrolase I, AAV-NRTN: AAV–Neurturin. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper.)

activity of AADC [63]. Hence, transfer of the gene encoding AADC into STN (STN AAV-AADC) or other basal ganglia nuclei could increase AADC synthesis, consequently leading to enhancement of dopamine level [64]. Fan et al. stated that the simultaneous transduction of serotype-2 rAAV vector encoding AADC and Tyrosine Hydroxylase (TH) into the striatum (St rAAV2-AADC, and St rAAV2-TH) of 6-OHDA-lesioned rats enhanced L-dopa and dopamine synthesis more than St rAAV2-TH alone, and led to noteworthy decreases in apomorphine-induced rotational rate [65]. Parallel outcomes with an emphasis on increased dopamine production along with increased tetrahydrobiopterin (BH4) levels were achieved by the same team using a cocktail treatment of STN AAV-AADC, STN AAV-TH, and STN AAV-CH1 in 6-OHDA-lesioned rats [66]. Similarly, Azzouz and colleagues found that STN AAV-AADC, STN AAV-TH, as well as STN AAV-CH1 (STN AAV GTP cyclohydrolase 1) in a single lentiviral vector can lead to the constant expression of AADC, TH, CH1, and effective improvement of behavioral symptoms in 6-OHDA-lesioned rats; however, it is unfortunate that the expression of these enzymes in the striatum was detected for up to 5 months [23]. Furthermore, it has been revealed that delivery of the TH gene might be due to the overproduction of L-dopa thereby causing the delivery of higher degrees of dopamine, and eventually exacerbate motor disorders [67]. Unlike the suggestions of a different strategy using peripheral Ldihydroxyphenylalanine administration after STN AAVAADC by Leff and coworkers, detected transgene expression in the striatum for at least one year [68]. Some studies have shown the persistent expression of AADC with a 30% or more increases of the AADC tracer by [18F]fluoro-L-mtyrosine (FMT)-PET (FMT-PET) uptake in putamen or STN

AAV-AADC-treated individuals [22, 69-71], nonetheless, three cases of intracranial hemorrhages have also been reported [70]. Reduced levodopa dose, safety, and improvement of AADC activity with no neuroinflammation symptoms or reactive gliosis for at least 8 years are introduced as the advantages of STN AAV-AADC [40, 72]. It was suggested that the primary immunization with rAAV may limit the reduction of transduced gene expression in STN AAV2AADC-treated rats [73]. Unlike AAV2, other study stated that AAV-5 does not affect the humoral immune response [74]. Finally, the small size of the AAV (4kbp) is considered as another drawback which restricts the transmission of DNA to around 4 kb. 2.2.3. Lenti-AADC/TH/GTP-CH1 AADC, TH, and GTP-CH1 (Guanosine TriphosphateCyclohydrolase I) are three enzymes expressed in nigral neurons and play the crucial role in the synthesis of dopamine from tyrosine. AADC, TH, and GTP-CH1 catalyze L-DOPA to dopamine, amino acid L-tyrosine to L-3,4dihydroxyphenylalanine (L-DOPA), and Guanosine Triphosphate (GTP) to 7,8-dihydroneopterin triphosphate (DHNTP), respectively. Then, 6-pyruvoyltetrahydropterin synthase (PTPS), aldose reductase, and Sepiapterin Reductase (SR) catalyzes DHNTP, 6-Pyruvoyl-Tetrahydropterin (PTP), and sepiapterin to PTP, sepiapterin, and eventually BH4 as the cofactor of TH, respectively [75-77]. Therefore, transfer of the gene encoding AADC, TH, and GTP-CH1 into STN (STN AAV-AADC, STN AAV-TH, and STN AAV-GTPCH1) can induce ectopic dopamine synthesis and may be able to compensate for the amount of lost dopamine. As previously mentioned, Fan et al. (1998), Shen et al. (2000), and Azzouz and colleagues (2002) demonstrated the


treatment for PD without any clinical or systemic neurotoxicity [90, 91]. In a double-blind, phase 2 randomized trial, intraputamenal delivery of CERE-120 in 58 patients with advanced PD not only did not improve the motor UPDRS scores but also led to serious unwanted events including five developed tumors [21]. The same team also reported the beneficial effects of intraputamenal CERE-120 on the offmedication motor UPDRS scores and dyskinesia in 2008 [92]. Moreover, delivery of a single dose Nerve Growth Factor (NGF) (AAV2-NGF; CERE-110) and CERE-120 led to targeted-expression of bioactive protein in the monkeys and continued for at least 20 months for NRTN without any safety issues or antibody response to the protein [93]. Postmortem investigation has confirmed the lack of NRTN expression in the SNc in PD, whereas strong expression of NRTN and increased TH immunoreactivity in all monkeys following intraputamenal CERE-120(Put CERE120) treatment [94]. Alone or simultaneously, SNc or STN CERE-120 (SNc CERE-120 or STN CERE-120) delivery was conducted in 6-OHDA-lesioned rats and the results indicated that the delivery of SNc CERE-120 alone is sufficient in the regeneration and production of greater numbers of dopaminergic neurons and distribution of NRTN within the targeted nigrostriatal neurons [95]. On the other hand, it has been emphasized that bilateral Put or SNc plus Put CERE120 delivery is possible and safe [96, 97]. The effectiveness of bilateral treatment with SNc and Put CERE-120 in advanced patients with PD were compared with sham surgery group in a randomized, double-blind, and controlled trial. Data analysis showed that the SNc and Put CERE-120 delivery were not superior to sham surgery [98].


beneficial effects of STN AAV-AADC, STN AAV-TH, and STN AAV-GTP-CH1 in 6-OHDA-lesioned rats [23, 65, 66]. Furthermore, it has been revealed that the Cos7 cells expressing AADC, TH, and GTP-CH1 and intrastriatal transduction of these genes (STN AADC/TH/GTP-CH1) enhance dopamine production in vivo and ex vivo [78, 79]. In 2009, Jarraya et al. illustrated increased dopamine production and noteworthy behavioral recovery in MPTP-lesioned macaque monkeys using intrastriatal delivery of a tricistronic lentiviral vector based on Equine Infectious Anemia Virus (EIAV) encoding AADC, TH, and GTP-CH1 in a single vector (EIAV-AADC-TH-GTP-CH1; named ProSavin), which continued up to 12 months without related dyskinesias [80]. In the following, an open-label, dose escalation, uncontrolled, phase 1/2 trial was conducted in 15 PD patients in third stages of the Hoehn & Yahr classification via ProSavin. All bilateral and intrastriatal ProSavin (STN ProSavin)-treated patients received three doses (low, mid, and high) in separate cohorts and were assessed with UPDRS (part III; off medication) scores. Significant improvement in motor UPDRS scores without any notable adverse events was observed in all patients at 6 and 12 months compared with baseline [81]. It was also claimed that ProSavin is safe and tolerable in patients with advanced PD.

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2.2.4. AAV–GDNF and AAV–NRTN (CERE-120)

Glial-derived Neurotrophic Factor (GDNF) and Neurturin (NRTN) are two neurotrophic factors with common functional abilities used to promote the survival and differentiation of nigrostriatal dopaminergic neurons both in vitro and in vivo [82-85]. It has been suggested that NRTN can promote the axonal regeneration, striatal dopamine levels, and reduce the methamphetamine-induced rotational rate in the 6-OHDA-lesioned rats [26]. Although GDNF and NRTN have common structural and functional similarities, direct delivery of each one into lateral cerebral ventricles leads to differential effects in vivo. GDNF-treated animals showed increased levels of dopamine utilization in the ventrolateral and mediodorsal striatum, whereas NRTN-treated animals showed increased levels only in the ventrolateral striatum. Weight loss and allodynia are also reported with GDNF administration but neither weight loss nor allodynia was detected with NRTN [86]. Kordower and colleagues (2006) hypothesized that the delivery of NRTN gene into the STN and SNc can preserve motor function in MPTP-induced hemiparkinsonian monkeys. They stated that the infusion of AAV2 vector encoding human NRTN (AAV–NRTN; also named CERE-120) can improve motor deficiencies by 80 to 90% (Since 4 to 10 months) and preserve nigrostriatal dopaminergic neurons [87]. Similar results were achieved by the CERE-120 delivery into the caudate and putamen in aged rhesus monkeys model of nigrostriatal dopamine deficiency [88]. CERE-120 delivery to the striatum (STN CERE-120) protected nigrostriatal dopaminergic neurons and improved motor function in 6-OHDA-lesioned rats for at least 6 months [89]. Parallel outcomes were realized by the same team using bilateral STN CERE-120 delivery. Herzog and coworkers (2007 and 2009) stated that STN CERE-120 delivery could enhance long-lasting expression (1-year) of NRTN and TH within the STN and SNc of rhesus monkeys. They also revealed that CERE-120 could be a novel safe

2.2.5. α-Synuclein Silencing

As mentioned previously, α-syn is known as the chief element of LBs encoded by the SNCA gene and is a chief player in both sporadic and familial cases of PD. The overexpression of α-syn leads to protein misfolding and its aggregation, dopaminergic cell loss and eventually LBs formation [99, 100]. Hence, downregulation or normalization of the α-syn level is considered to be a strategy for treatment of PD. On the contrary, delivery of α-syn into SNc leads to loss of nigral dopaminergic neurons, reduction of dopamine and TH levels, and ultimately the emergence of Parkinson-like neurodegeneration [101-103]. Similarly, it has been revealed that the duplication and triplication of α-syn locus cause PD [104, 105]. Interestingly, the dinucleotide repeat sequence (REP1) allele-length variation of the SNCA gene promoter is associated with susceptibility to PD [106]. Delivery of α-syn ribozyme via an AVV vector (AVV-αsynRz) into the SNc of MPTP-lesioned rats considerably protected TH-positive degeneration [107]. Similarly, silencing ectopic expression of SNCA using AAV-SNCA with or without a short hairpin RNA (shRNA) was conducted by infusion into rat SNc. Despite the behavioral improvement in the treated groups, high doses of shRNA-SNCA were toxic to dopaminergic neurons [108]. It has been shown that the RNA interference (RNAi) effectively diminish the expression of α-syn in both in vitro and in vivo [109-111]. Sapru et al. stated that the human and rat α-syn silencing is achievable in vitro and in vivo using lentiviral-mediated RNAi


[112]. McCormack and colleagues designed a small interfering RNA (siRNA) against α-syn (siRNA-α-syn) and infused it into the left SNc of squirrel monkeys. From their results, significant (40-50%) suppression of α-syn was observed in the left vs. untreated right hemisphere, and siRNA-α-syn did not cause neuroinflammation or reduction of striatal dopamine concentrations [113]. Another study introduced a newly developed siRNA system which confers a moderate level of gene silencing by the name of expression-control RNAi (ExCont-RNAi). This team claimed that ExContRNAi-treated PD patients showed noteworthy improvement in their motor scores and announced ExCont-RNAi as a novel therapeutic method for PD with SNCA overexpression [114]. This is contrary to the report that RNAi-mediated αsyn silencing in the SNc leads to motor dysfunction and degeneration of nigral dopaminergic cells [115, 116]. 2.2.6. PRKN Gene Delivery

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been shown that targeted correction of LRRK2 G2019S mutation in hiPSCs ameliorates neurite outgrowth, basal autophagy, and the increased α-syn and Microtubule-Associated Protein Tau (MAPT) expression in the mutated cells [142]. Likewise, Dansithong and colleagues (2015) showed that the missense mutation of SNCA gene can be genetically corrected by ZFNs in vitro [143]. It has also been demonstrated that LRRK2 mutant iPSC-derived dopaminergic neurons are more susceptible to oxidative stress than normal neurons [144, 145]. Liu et al. (2012) differentiated iPSC lines from patients with the Lamin A (LMNA) Mutation into Neural Stem Cells (NSCs) with or without homologous recombination-based gene correction. They observed that progressive nuclear aberrations of the PD-derived NSCs were absent in the corrected NSCs [146]. 3. STEM CELL-BASED THERAPIES FOR PD Over the past decades, stem cell-based therapies have made an increasingly smart therapeutic possibility to investigate and treat neurodegenerative diseases [147-150]. Replacing the lost cells is one of the main goals of this strategy. In this regard, replacing the dopamine-producing cells could help in the treatment or improvement of the disease. It was shown years ago that intra-parietal cortex transplantation of ventral mesencephalic tegmentum is able to generate new dopaminergic neurons in the 6-OHDA-lesioned rats [151]. However, the first clinical trial in candidates with PD was not performed by the human fetal mesencephalic tissue. Preclinical studies demonstrating that the human mesencephalic dopaminergic neurons from 6.5-8 week old fetuses engrafted to the non-immunosuppressed 6-OHDA-lesioned rats may be sufficient to renovate and reinnervate the striatum and improve behavioral deficits [152].


PRKN is known as a key gene involved in autosomal recessive juvenile Parkinsonism, familial, and sporadic PD [117, 118]. PRKN also plays a crucial role in autophagy and the selective deletion of damaged mitochondria, consequently hindering the elimination of impaired mitochondria by the PD patients [119]. Paterna and coworkers observed that the SNc AAV-PRKN in MPTP-lesioned mice causes more living dopaminergic neurons and rotational rate improvement than the control [120]. Yasuda et al. also used the same strategy in MPTP-lesioned mice and stated that SNc AAV-PRKN delivery prevents motor deficits and dopaminergic cell loss [121]. Moreover, SNc Lenti-PRKN, two weeks prior to striatal 6-OHDA lesioning, led to the remarkable protection of dopaminergic cells and improved amphetamine-induced rotation rate [122]. Likewise, SNc LentiPRKN delivery caused overexpression of PRKN in an α-syn rat model of PD thereby significantly preserving TH-positive cell bodies and terminals in SNc and St, respectively [123]. Yamada and colleagues stated similar results with SNc rAAV2–PRKN and emphasized the effectiveness of this strategy against alpha-synucleinopathy [124]. Subsequently, the same team failed to repeat the protective effects of STN rAAV1–PRKN delivery in macaque monkeys, nonetheless, these conflicting findings may be related to serotypes (AAV1 vs. AAV2) or the injected brain regions (SNc vs. STN) [125].


2.2.7. Genome Editing Genome editing provides a powerful procedure to development of isogenic disease models and the repair of diseaserelated mutations, in vitro. Though studies have been reported the possibility of performing genome editing in human pluripotent stem cells (hPSCs) with Zinc Finger Nucleases (ZFNs) and Transcription Activator-like Effector Nucleases (TALENs) systems [126-135], Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) system especially CRISPR/Cas9 protein (CRISPR/Cas9) is known as a simple and adaptive tool for modeling human cells for such purposes [136-141]. Soldner et al. (2011) generated isogenic stem cell models of PD by correction of an SNCAA53T mutation in PD patient-derived human induced pluripotent Stem Cells (hiPSCs) or by knock-in of this mutation in a Human Embryonic Stem Cell (hESC) line [131]. It has

3.1. Different Sources of Stem Cells for the Treatment of PD In recent years, several sources of stem cells have been established for the treatment of PD (Fig. 3), each of which has several advantages and disadvantages (Table 1). Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs), induced Pluripotent Stem Cells (iPSCs), fetal Ventral Mesencephalic Tissue (VMT; contains nigral dopaminergic neurons), and Neural Stem Cells (NSCs) are the most common sources that hold a great hope for the regeneration of the lost dopaminergic cells [153-156]. Each of these cell sources has some advantages and disadvantages that bring about specific results. Risk of tumor formation and genomic instability are the main limitations of using ESCs and iPSCs. In contrast, MSCs have slight immunogenic responses due to lack of Major Histocompatibility Complex class II (MHC-II) molecules [157, 158]. 3.1.1. Mesenchymal Stem Cells (MSCs) MSCs are a series of multipotent stem cells which are generally isolated from bone marrow [159-165], placenta [166], amniotic fluid [167], umbilical cord blood [168, 169], and adipose tissue [170-174]. MSCs can differentiate into adipocytes, neuron, skeletal myocytes, osteoblasts, tenocytes, chondrocytes, as well as the visceral mesoderm cells. These cells possess low tumorigenicity and immune

blastocyst

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Fig. (3). Different sources of stem cells for the treatment of PD. Table 1.

The potential for differentiation, advantages and disadvantages of different sources of stem cells for the treatment of PD.

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Neurons, Astrocytes, and Oligodendrocytes

1.

Low tumorigenicity and immune responses than ESCs and iPSCs

1.

Risk of graft-induced dyskinesias (GIDs)

2.

Limited differentiation in vivo

2.

Able to form neurons, astrocytes, and oligodendrocytes

3.

PD-like symptoms

4.

Failure to differentiate into the three germ layer cells

1.

Few therapeutic effectiveness in humans

2.

Failure to differentiate into the three germ layer cells

MSCs

ESCs

iPSCs

Adipocytes, osteoblasts, tenocytes, chondrocytes, skeletal myocytes, neuron, and the visceral mesoderm cells

Three germ layer cells

Three germ layer cells

1.

Low tumorigenicity and immune responses than ESCs and iPSCs

2.

A genuine and accessible cell source

3.

Improvement of cognitive and motor performances

1.

High proliferative and differential potency

1.

Risk of tumor formation

2.

Can generate dopaminergic neurons

2.

Genomic instability

3.

Able to differentiate into the three germ layer cells

3.

Immunogenic responses and ethical issues

1.

High proliferative and differential potency

1.

Risk of tumor formation

2.

Can generate dopaminergic neurons

2.

Genomic instability

3.

Able to differentiate into the three germ layer cells

4.

No immunogenic responses and ethical issues

responses than ESCs and iPSCs due to lack of MHC-II molecules [157, 158]. Although MSCs lack the limitations of ESCs and iPSCs, they have relatively few therapeutic effectiveness in humans. However, MSCs have been accepted as

promising candidates for cell therapy. Some reports have emphasized on the neuroprotective and neurorestorative beneficial effects of MSCs such as Bone Marrow-Derived MSCs (BMSCs) and adipose-derived mesenchymal stromal



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germ layer cells including dopaminergic neurons [147, 205, 206]. These unique features of ESCs make them an outstanding candidate for the generation of dopamine-producing cells. However, due to some limitations such as tumorigenicity and immunogenic responses, the use of undifferentiated forms of these cells has many problems. Even though low doses of undifferentiated mouse ESCs (mESCs) leads to developed severe teratoma-like tumors, some animals died before completion of behavioral evaluation [207]. A series of studies have reported the eﬃcient induction of hESCs and mESCs into dopaminergic neurons [208-212]. Lee and coworkers (2000) presented an efficient method for the derivation of dopaminergic and serotonergic neurons from mESCs in vitro [208]. Kawasaki and colleagues (2000) showed that PA6 stromal cells promote neural differentiation probably by suppressing the effects of Bone Morphogenetic Protein 4 (BMP4) as an antineuralizing morphogen [209]. Other researchers have also tried to improve in vitro and/or in vivo induction or optimization of dopaminergic neurons from ESCs [213-219]. Likewise, it has been demonstrated that BMP inhibitor Noggin increases transformation rate of hESCs to dopaminergic neurons on PA6 stromal cells [220]. Although ESCs have the high proliferative potency to differentiate into the three germ layer cells including dopaminergic neurons which lead to significant improvement of clinical symptoms, genomic instability, immunogenic responses and the possibility of graft rejection, tumorigenicity and ethical issues are the limitations of ESCs. Hence, due to these drawbacks, no clinical trials have been accomplished yet with ESCs in PD patients.

3.1.2. Neural Stem Cells (NSCs)

3.1.4. Induced Pluripotent Stem Cells (iPSCs)

NSCs are multipotent, self-renewing stem cells that give rise to different neural cells such as neurons, dopaminergic neurons, oligodendrocytes, and astrocytes [189-192]. NSCs can be harvested from the fetal, neonatal, or adult brain regions such as SVZ and the Subgranular Zone (SGZ) of the dentate gyrus, as well as the Subependymal Zone (SEZ) of the lateral ventricles [193-196]. Clinical trials have shown that bilateral intraputamenal transplantation of VMT-derived dopaminergic neurons leads to some clinical benefits in younger but not in older PD patients, however, GIDs and off medication have also been reported as side effects [197, 198]. Moreover, long-term follow-up of two PD patients who had long-term (11-16 years) survival of transplanted VMT has been shown α-syn positive LBs in grafted neurons [199]. NSCs can be directly transplanted through the needle into a specific region like striatum or SNc. Nonetheless, BBB is an effective barrier to intravascular transplantation of NSCs [200]. Behavioral improvement has been shown in MPTP-lesioned Parkinsonian primates following injection of NSCs into the right SNc and the right and left caudate nuclei [201]. Intrastriatal transplantation of NSCs into the intact or 6-OHDA-lesioned rats led to the marked expression of Aromatic L-Amino Decarboxylase (AADC), while a significant number of the cells did not express TH [202]. Overall, NSCs exhibits low proliferation and differentiation capacities and lose their features after continuous passages [203, 204].

Since iPSCs were introduced by Nobel Prize-winning Shinya Yamanaka in August 2006, a tremendous transformation occurred in cell biology [221]. Afterward, Oct4, Sox2, Klf4, and c-Myc pluripotency factors were known as Yamanaka factors for induction of adult somatic cells to a novel type of pluripotent stem via retroviral or lentiviral systems cells called iPSCs [221-223]. Subsequently, Thomson and colleagues (2007) illustrated another protocol (OCT4, SOX2, NANOG, and LIN28) to induction of human somatic cells to iPSCs that exhibit the important characteristics of ESCs [224]. Genome-wide analysis with histone H3K27me3 and H3K4me3 modifications revealed that a slight difference exists between iPSCs and ESCs, and these cell lines are extremely similar to each other, however, the problem of the immunogenic response is almost resolved in iPSCs [225]. Thereafter, several studies used these two protocols to produce iPSCs and their differentiation into the dopaminergic neurons for the treatment or improvement of motor and nonmotor symptoms of PD [220, 226-234]. Some studies have also revealed that the autologous transplantation of iPSCsderived dopaminergic neurons can survive in the brain without immunosuppression and/or improve motor and nonmotor symptoms of PD [228, 231-236]. Although iPSCs have had almost slight problem in ethical issues, immunogenic responses and the possibility of graft rejection, several problems remain to be solved. First, it has been shown that the ectopic overexpression of Klf4, Oct4, Sox2, and c-Myc can lead to formation of breast tumors [237], dysplasia in epithelial cells [238], mucinous colon carcinoma [239], and


cells [171-173], though contradictory results have also been reported [175]. It has been shown that grafted human MSCs (hMSCs) possess protective effects against nigrostriatal degeneration in human and 6-OHDA-lesioned rats [176-184]. Blandini and colleagues (2010) demonstrated that grafted hMSCs lead to increased number of striatal dopaminergic ⁺ terminals and TH nigral cell bodies in 6-OHDA-lesioned rats, thereby protecting nigrostriatal degeneration [176]. The neuroprotective effects and rescue of dopaminergic neurons were presented in MPTP-lesioned models [161, 185]. It has been shown that intravenous transplantation of MSCs can lead to inactivation of microglia and inhibition of dopaminergic cells death in MPTP-lesioned mice [186]. It has also been revealed that intrastriatal transplantation of dopaminergic-like cells derived from BMSCs successfully reduced the apomorphine-induced rotational rate in 6-OHDAlesioned mice. These cells had survived four months posttransplantation in the striatum and expressed TH, and some of them immigrated toward the SNc [187]. Furthermore, it is elucidated that hMSCs graft meaningfully augmented neurogenesis in both the Subventricular Zone (SVZ) and SNc of MPTP- and 6-OHDA-lesioned animal models, and lead to increased differentiation of neural precursor cells into dopaminergic neurons in the SNc [161, 188]. Conversely, Neirinckx and coworkers (2013) have stated that BMSCs are not able to replace lost neurons in MPTP-lesioned mice [175]. Despite considerable beneficial effects of MSCs transplantation in improving motor and non-motor symptoms in PD models, however, the underlying mechanisms have not been fully understood.

3.1.3. Embryonic Stem Cells (ESCs) ESCs are inner cell mass-derived pluripotent stem cells with high proliferative potency to differentiate into the three


the formation of human cancers [240], respectively. Second, 209 of 593 iPSCs genes were expressed in tumor and cancer tissues. Third, 5 oncogenes especially RAB25 were overexpressed in the iPSCs and iPSC-differentiated cells, respectively [241]. Therefore, tumorigenicity and formation of cancers are associated with genes. Furthermore, RAB25 encourages survival of cancer cells under various stress situations [242]. Another concern on this issue is the combination of viral structures within the host genome which can lead to teratoma formation [243]. 3.1.5. Directly Induced Dopaminergic Neurons (iDNs)

4. BRAIN STIMULATION 4.1. Transcranial Magnetic Stimulation (TMS) TMS is a noninvasive electromagnetic stimulation that has recently been used for the induction of neuroplasticity of the cerebral cortex for the improvement of neurological and psychiatric disorders like PD [261-279], Alzheimer’s disease (AD) [280-285], stroke [286-290], depression [291-294], schizophrenia (Scz) [295-298], obsessive-compulsive disorder (OCD) [299-301], epilepsy [302-306], and mood disorder [307-313]. Single pulse TMS releases a single pulse at a certain time, while repetitive pulse TMS (rTMS) deliver repeated single pulse to a specific brain region [314]. Some reports have stated the beneficial effects of rTMS on cognitive, psychological, or motor performances in PD patients [261, 272-274, 276, 277, 315-318], whereas, others have reported neutral (neither beneficial nor adverse effects) [264, 278] or adverse [269, 271] effects of rTMS. For the first time, Pascual-Leone and colleagues (1994) reported that subthreshold 5 Hz rTMS over the motor cortex improved the reaction time and movement time without affecting the rate of error in six patient with PD [261]. It has been elucidated that 1 and 5 Hz rTMS over the Motor hand area (M1) can improve dyskinesias and bradykinesia in PD patients, respectively [265, 274, 318]. Mally and coworkers (2004) concluded that 1 Hz rTMS for 7 days can postpone the progression of the disease than those treated with selegiline + levodopa [316]. The long-lasting motor UPDRS scores improvement has also been reported by rTMS in PD patients [266, 267, 274, 277, 317], and walking performance [272]. The motor improvement and the reduced methamphetamineinduced rotational rate have also been approved in 6-OHDAlesioned rats [276]. Conversely, it has been revealed that subthreshold 5-Hz rTMS over the motor cortex does not reliable or actually cause therapeutic effects on the movement of PD patients [262]. In addition, the cerebellar-like terminal and postural tremor may be induced by TMS in normal individuals [263]. Also, it has been demonstrated that low and/or high-frequency rTMS has no therapeutic effects and fail to improve motor performance in patients with PD [264, 278]. Abnormal M1 responses and subclinical worsening of the preliminary movement have been reported following rTMS over the primary motor cortex and supplementary motor area, respectively [269, 271]. A headache, ailment and burn at the site of stimulation, neck pain, seizure or convulsive syncope, mania, delusions, and vagal reactions are the reported side effects of rTMS [319-335]. However, further studies are required to identify the exact cellular and molecular mechanisms of rTMS.


Transdifferentiation or lineage switching (as a class of metaplasia; cell switching from a specific fate to another) is defined as direct transformation of a somatic cell to another without passing a pluripotent phase [244, 245]. It was a great success so that fibroblasts would be directly reprogrammed to the target cells. It has been previously illustrated that mouse and human fibroblasts can be directly transformed to functional dopaminergic neurons without leaving a pluripotent phase [246-253]. A series of these studies have reported successful production of dopaminergic neurons from the mouse and/or human fibroblasts using different combinations of Mash1 (Ascl1), Myt1l, Nurr1 (Nr4a2), Brn2, Ngn2, Lmx1a, Sox2, and Pitx3 transcription factors [246, 250, 252, 254]. Park and coworkers (2006) used Mash1, Mytl1, Brn2, Lmx1a, Foxa2 transcription factors for the induction of fibroblasts to dopaminergic cells [254]. Caiazzo and colleagues (2011) showed that Mash1, Nurr1, and Lmx1a transcription factors can directly induce mouse and human fibroblasts to functional dopaminergic neurons [246]. Similar results have been reported by Pfisterer et al. (2011) using Ascl1, Brn2, and Myt1l transcription factors [252]. Liu et al. (2012) also identified that Mash1, Ngn2, Sox2, Nurr1, and Pitx3 transcription factors can efficiently convert human fibroblasts into dopaminergic-like cells [250]. In contrast, it has been revealed that Ascl1 and Pitx3 are sufficient in the transformation of fibroblasts into an immature dopaminergic cell fate [247]. Although this technique is faster compared to iPSC-derived dopaminergic neurons, several difficulties remain to be solved. It has been elucidated that sufficient numbers (200,000~400,000) of TH-positive cells are required to obtain a relatively acceptable result [255-260]. The iDNs produced by the procedure of Park et al. are not able to express all the specific markers of midbrain dopaminergic neurons and release the dopamine. Additionally, the efficacy of produced neurons has been reported to be about 10% [254]. The iDNs produced by Pfisterer group could secrete dopamine, however, their iDNs phenotype was immature and the efficacy of the produced neurons was also low [252]. Moreover, not all the specific markers of midbrain dopaminergic neurons could be expressed. The phenotype of iDNs produced by Caiazzo team was more similar to midbrain dopaminergic neurons. However, the transcriptome study of these iDNs, as in the two previous groups, showed a major difference with the midbrain-derived dopaminergic neurons [246]. As another limitation and safety concern, the fibroblasts of PD patients may carry the genomic mutations such as PRKN, SNCA, GBA, and LRRK2.

Ghamgosha et al.

4.2. Deep Brain Stimulation (DBS) DBS is an invasive neurosurgical technique introduced in 1987 as a clinical handling for the treatment of movement disorders, particularly for moderating the progressive symptoms of PD [1, 336-338]. DBS has now been extensively known as an effective method in advanced stages of PD. Usually, the Subthalamic Nucleus (STN), Ventral Intermediate nucleus of the thalamus (VIM), and Globus Pallidus Interna (GPi) are the key targets for DBS in PD [1]. It has previously been revealed that unilateral subthalamotomy including the caudal zona incerta can lead to significant improve-


215

PRKN, stem cell-based therapies, M1 rTMS, STN DBS, GPi DBS, VIM DBS, and M1 tDCS, it seems that these hopes are not sufficient to treat the disease. As previously mentioned, the mean level of improvement by STN DBS was more than that seen with STN AAV2GAD gene therapy. Nevertheless, DBS as an invasive neurosurgical technique is done in severe stages of the disease, when more than 80% of dopaminergic neurons were lost. The small size of the AAV is considered as another drawback which restricts the transmission of DNA to around 4 kb. It has been described that RNAi-mediated α-syn silencing in the SNc leads to the motor dysfunction and degeneration of nigral dopaminergic cells. Although ESCs and iPSCs have high proliferative potency to differentiate into the three germ layer cells including dopaminergic neurons, genomic instability, immunogenic responses and the possibility of graft rejection, tumorigenicity and ethical issues are the limitations of these cell lines. Also, the fibroblasts of PD patients may carry genomic mutations such as PRKN, SNCA, GBA, and LRRK2. Although MSCs do not have the limitations of ESCs and iPSCs, they have relatively few therapeutic effectiveness in humans. Several breakdowns and side effects were described for rTMS and DBS. tDCS seems to be less complicated than rTMS and DBS, however, its effectiveness is also lower. Altogether, the effective treatment for PD has mostly failed because of these limitations and the late diagnosis of the disease. A day when scientists can acquire enough knowledge to prevent and treat this disease is sincerely hoped for.


ment of contralateral motor symptoms in patients with advanced PD [339]. Subsequently, attempts of Blomstedt and colleagues (2009) led to important findings regarding the potential of the posterior subthalamic area including the caudal zona incerta as a DBS target in PD [340, 341]. It has been frequently shown that DBS of STN, GPi, and VIM (STN DBS, GPi DBS, and VIM DBS, respectively) can lead to relieve of resting and/or action tremors in patients with PD [340, 342-352]. Furthermore, constant improvements of bradykinesia, rigidity, and motor symptoms were also reported following STN and/or GPi DBS [353-358]. Although constant improvements in tremor, bradykinesia, rigidity, and motor symptoms have been stated following STN, VIM, or GPi DBS, however a series of complications have also been reported. Pneumocephalus, epileptic seizure, balance instability, anisocoria, hematoma, dyspnea, airway obstruction, infection, arterial hypertension and hypotension, bradycardia, tachycardia, gait disorders, cognitive decline, speech difficulty, and depression have been reported as the failures and side effects of DBS [351, 359-363].


4.3. Transcranial Direct Current Stimulation (tDCS)

Brain stimulation via feeble direct current has been shown to modulate excitability and plasticity of cortical and subcortical tissues [364, 365]. The use of feeble direct stimulation by applying galvanic currents date back to 1804 [366368]. tDCS is a non-invasive, safe, cheap, painless, and welltolerated brain stimulation technique that utilizes low direct current to stimulate a specific area of the brain [369]. While anodal tDCS acts to excite neural activity, cathodal tDCS inhibits or diminishes its activity. The therapeutic potential and long-lasting improvement of motor UPDRS scores, reaction time, bradykinesia, and dyskinesia have been reported by anodal tDCS of the primary motor cortex (M1) [370-377]. It has also been revealed that anodal tDCS of the DLPFC leads to improved executive functions including working memory in patients with PD [378, 379]. Tanaka et al. stated that cathodal but not anodal tDCS can significantly increase extracellular dopamine levels in the rat striatum [380]. It has been demonstrated that anodal but not cathodal tDCS of the motor cortex improves survival and integration of dopaminergic neurons in 6-OHDA-lesioned rats [381]. Although tDCS has some side effects like other brain stimulation techniques, these effects are relatively mild, transient, and less than the other methods. Some reports have presented a series of side effects like headache, nausea, and insomnia after tDCS [382, 383] however, not all, but some of the side effects may be due to the protocol used and the user's precision. CONCLUSION In this review, a detailed description of the cellular, molecular, and clinical therapeutic advances for the treatment of PD was presented and the advantages and disadvantages of these methods were emphasized. Despite the very respectable advances in these cutting-edge therapies, numerous problems still exist that has incapacitated the definitive treatment of the disease. Although numerous hopeful results emphasize the effectiveness of STN AAV2-GAD, STN AAV-AADC, STN AAV-TH, STN AAV-GTP-CH1, STN ProSavin, STN CERE-120, siRNA-α-syn, SNc rAAV2–

CONSENT FOR PUBLICATION Not applicable.

CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS

This review was supported by a grant from the Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran (grant no. BMSU.961010). REFERENCES [1] [2]

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