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Shalaby, K.E.;  El-Agnaf, O.M.A. Gene Therapy for Parkinson’s Disease. Encyclopedia. Available online: (accessed on 30 November 2023).
Shalaby KE,  El-Agnaf OMA. Gene Therapy for Parkinson’s Disease. Encyclopedia. Available at: Accessed November 30, 2023.
Shalaby, Karim E., Omar M. A. El-Agnaf. "Gene Therapy for Parkinson’s Disease" Encyclopedia, (accessed November 30, 2023).
Shalaby, K.E., & El-Agnaf, O.M.A.(2022, August 10). Gene Therapy for Parkinson’s Disease. In Encyclopedia.
Shalaby, Karim E. and Omar M. A. El-Agnaf. "Gene Therapy for Parkinson’s Disease." Encyclopedia. Web. 10 August, 2022.
Gene Therapy for Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a prevalence that increases steadily with age. Gene therapy is a modern medical practice that theoretically, and practically, has demonstrated its capability in joining the battle against PD and other complex disorders on most if not all fronts. 

neurodegeneration Parkinson’s disease gene therapy

1. Introduction

The high potential of gene therapy gives immense hope for curing thousands of diseases with limited treatment options, such as cancer and monogenic diseases [1][2]. Gene therapy is either carried out ex vivo, involving the genetic modification of cultured cells and transplanting them into the patient, or in vivo, involving the use of vectors to deliver nucleic acids (DNA, RNA, etc.) or genome-modifying components such as CRISPR-Cas to cells to correct a mutation or to regulate a gene’s expression. Gene delivery vectors can either be viral or non-viral. The former harnesses viruses’ natural ability to infect host cells with their genome and are genetically modified to remove pathogenic genes and replace them with the sequence of interest. The most commonly used viral vectors are lentiviruses and adeno-associated viruses (AAVs). Lentiviruses, a subspecies of retroviruses, integrate their cargo into the host’s genome, assuring long-term expression of the delivered gene, but carrying the risk of random insertional mutagenesis. While AAVs offer a rather limited carriage capacity (~4.5 kb), they are deemed large enough for most genes used in therapy. They are also considered a much safer alternative because their genomes exist as an independent episome in the transfected cell, and they are also capable of conferring long-term expression in non-dividing neurons [3][4]. Furthermore, the use of certain serotypes (e.g., AAV9) carries certain advantages, such the ability to cross the BBB [5], a major obstacle in the way of vectors to the brain.
Conventional gene therapy utilizes viral vectors for the delivery of therapeutic transgenes. The first viral-mediated gene therapy was approved for clinical use in 1990 for adenosine deaminase-severe combined immunodeficiency (ADA-SCID). In it, two young girls were treated with autologous T-lymphocytes genetically modified with retroviruses carrying a wild-type ADA gene ex vivo [6][7]. Evidence of modest feasibility encouraged subsequent gene therapy trials to take place, to which major limitations ensued. For example, gene therapy trials for SCID resulted in the development of therapy-related leukemia in several young children, leading to the death of one patient [8][9]. Investigations of the possible cause of leukemia revealed insertional mutagenesis of the therapeutic gene into a proto-oncogene locus [10]. Consequently, various bodies modeled by the US Recombinant DNA Advisory Committee and the Food and Drug Administration have been established to acknowledge this risk and to standardize protocols for gene therapy in humans globally [11].
Non-viral vectors are synthetic, which gives them a unique flexibility to be customized for use from a range of different compounds, such as lipids and proteins. The components of synthetic vectors are inspired from the composition of viral envelopes that enable viruses to specifically bind to host cells. However, they offer a safer alternative to viral vectors with possibly lesser mutagenic and immunogenic responses in the host [12]. It has been shown that by integrating a fragment derived from the rabies virus glycoprotein (RVG), these vectors can be modified to cross the BBB and deliver their cargo to specific neuronal cells for the treatment of Parkinson’s disease (PD) [13][14]. Thus far, all gene therapy clinical trials for PD have been carried out using viral vectors, since non-viral vectors need to be optimized to provide equal delivery efficiency to viral vectors.
Gene editing approaches, such as using CRISPR, are capable of inducing genetic insertions and corrections at a specific locus and offer an alternative to introducing a therapeutic gene into a random genomic locus. The emergence of such approaches further helps to overcome the critical limitation of insertional mutagenesis.

2. Gene Therapy Trials for PD

Most gene therapy clinical trials have fulfilled Phase I, safety and efficacy profiles, but the majority failed when advanced to controlled, blinded Phase II trials to achieve results beyond placebo effect or better than those seen with current treatments (Table 1). Importantly, these studies represent a proof of concept of how PD can be tackled at the genetic level. Ongoing trials focus either on symptomatic benefit through balancing physiological basal ganglia circuitry or enhancing the dopamine biogenesis pathway, or on disease modification through providing neuronal protection or preventing α-synuclein aggregation or accumulation. The principles, progress and results of these trials are discussed below to highlight how gene therapy could be used to tackle PD on these different levels, emphasizing its broad scope of intervention.
Table 1. Current status of gene therapies for Parkinson’s disease.

2.1. Restoring the Physiological Balance of the Basal Ganglia

The loss of dopaminergic neurons in PD leads to a hyperactive STN, which can be reversed by injections of an agonist of γ-aminobutyric acid (GABA), the inhibitory neurotransmitter of the STN, as shown previously in non-human primate (NHP) PD models [26].


PD-like symptoms were alleviated in rat and NHP models via overexpression of glutamic acid decarboxylase (GAD), the enzyme involved in the synthesis of GABA, in the STN [27][28]. Two genetically distinct GAD isoforms, GAD65 and GAD67, were both used in a trial to increase GAD expression in the STN [15]. The trial’s aim was to increase GABA production and the inhibition of the STN, thus attaining the same effect of DBS and improving motor deficits. In Phase I, all patients who received a unilateral AAV2-GAD injection to the STN showed improvements on their unified Parkinson’s disease rating scale (UPDRS) scores which persisted throughout the 12-month duration of the study [15]. Subsequent positron emission tomography (PET) scans using [18F] fluoro-deoxyglucose as a tracer showed a significant reduction in glucose uptake in the thalamus of the treated side, indicating a reduction in thalamic metabolic activity, in line with the improved motor functions [15]. In a double-blinded Phase II trial, patients who received AAV2-GAD injection had improvements in UPDRS scores over the sham control group [16]. Although gene therapy ameliorated PD symptoms in these trials with no adverse events reported in any of the patients and effects persisting for a year [17], they showed no greater improvement over current standards of care. It is important to note that these studies serve as a proof-of-principle approach for a generally safe and efficacious operation for gene therapy which is valuable for optimizing the design of larger clinical trials in the future.

2.2. Enhancing Dopamine Synthesis

Dopamine is synthesized in dopaminergic neurons from the amino acid tyrosine derived through diet. Tyrosine is first converted to L-DOPA by tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC) converts L-DOPA to dopamine. Guanosine triphosphate cyclohydroxylase I (GCH1) is the rate-limiting enzyme in synthesizing the TH co-factor tetrahydrobiopterine (BH4). These enzymes are transported from the SNc to the striatum through the nigrostriatal pathway in an anterograde manner. In advanced PD, severe dopaminergic nerve loss is associated with a significant reduction in the activity of these enzymes in the striatum. In addition, as the disease progresses, L-DOPA dosage requirements for patients increase and the resulting elevated levels of dopamine outside the basal ganglia lead to dyskinesia.


Gene transfer of AADC has been used to enhance the pathway of dopamine biogenesis, by rescuing AADC levels dropping with the degeneration of nigral dopaminergic neurons [18][29][30][31][32][33][34]. After assessment in animal models [29][30][31], Phase I clinical trials using AAV2 [18][32][33] concluded that AAV-AADC gene transfer is safe and stable and patients showed clinical improvements in the first 12 months; however, this improvement slowly deteriorated. This was attributed to the restricted distribution of AADC expression, and the relatively small final volume of vector infused. Consequently, researchers have developed a novel mechanism of delivery, with the aim of increasing the coverage of the striatum, using an MRI-guided convection enhanced delivery (CED) to monitor the delivery of the transgene in non-human primates in real time [34]. Accurate positioning of the cannula was confirmed by MRI images indicating increased coverage of the targeted affected mid-brain neurons in all animals. Further assessment by immunohistochemical staining confirmed the increased expression of AADC in the SNc compared to control animals, which correlated with an increase in AADC concentration in the striatum, indicating successful axonal transport throughout the nigrostriatal pathway. Indeed, as this trial has achieved safety and efficacy and an MRI-CED delivery of AAV2-AADC, it should be assessed for efficiency in a human clinical trial.


A lentiviral-vector-based gene therapy aimed at increasing the efficiency of patients’ metabolism of L-DOPA, and thus decreasing the dose of L-DOPA required and avoiding treatment-related side effects [22][35]. Initially, triple gene transfer of CGH1, TH and AADC in a single lentiviral transcriptional unit was first demonstrated to successfully increase dopamine production and reduce motor asymmetry in rat models of PD [35]. Recently, in a dose-escalation clinical trial, patients who received the Lenti-TH-AADC-GCH treatment demonstrated dose-dependent improvements in their UPDRS scores after 12 months, with the group receiving the highest dosage displaying the most improvement [22]. The study was extended, and patients who were still part of the study showed further improvements after 24 and 36 months [22]. Overall, the trial achieved safety and efficacy, but no control group was included, and the improvements were within the placebo effect seen in other trials [22]. This trial, however, represents the first where lentiviral vectors have been successfully applied to the treatment of a neurological disorder. Moreover, this approach does not depend on dopaminergic neurons, but rather assumes that the transfected striatal neurons will develop the ability to synthesize dopamine. However, striatal neurons lack other mechanisms intrinsic to dopaminergic neurons, such as the capacity to store synthesized dopamine in synaptic vesicles and to take it back up after release through dopamine transporters, which is perhaps why there was no significant improvement.

2.3. Neuroprotection and Regeneration

The loss of SNc dopaminergic neurons caused by PD pathology results in the reduction in dopamine levels in the striatum. Thus, providing support and protection to dopaminergic neurons from degeneration is an attractive strategy to prevent the manifestation of downstream complications such as physiological imbalances, and symptoms such as rigidity and bradykinesia associated with the disease.


Gene therapy trials offering neuroprotection have focused primarily on the delivery of members of the glial cell family of ligands (GFLs), which are known to play a role in cell protection and survival [36]. For example, the delivery of neurturin (NRTN) to the putamen using AAV2 was well tolerated in a Phase I clinical trial [23], but no improvements in motor function were observed [24]. Analyses of postmortem tissue showed an increase in NRTN expression in the putamen; however, due to a failure of retrograde transport, it was not upregulated in the SN [37]. Moreover, no improvements in motor function were seen in a clinical trial using higher doses of AAV-NRTN to address this issue [25]. On another hand, in animal models, glial-derived neurotrophic factor (GDNF) expression protected nigrostriatal neurons and improved motor function. However, it was found that its long-term expression causes aberrant axonal sprouting and downregulation of TH [38][39]. GDNF is a growth factor that was the first GFL to be discovered, and it functions in promoting the survival of dopaminergic neurons [40]. Further studies demonstrated that injections of AAV-GDNF were well tolerated [41][42]; however, bilateral SN injections resulted in weight loss in aged monkeys [42]. Two ongoing Phase I clinical trials are currently testing the safety of bilateral injections of AAV2-GDNF into the putamen (NCT01621581 and NCT04167540). Importantly, a system whereby the expression of GDNF can be controlled after delivery was developed and showed neuroprotection and improvement in motor function in rodent models [43][44]. In this method, the destabilizing domain of E. coli dihydrofolate reductase was fused to GDNF and delivered to neurons using a lentiviral vector. The expression was controlled by the temporal administration of Trimethopram, a drug that crosses the BBB to stabilize the destabilizing domain and activate GDNF expression [43]. The treated group showed improved motor function and a higher level of TH expression than rodents receiving a normal GDNF transfusion. This chemical method sets an adaptable protocol using destabilizing domains to control the expression of other genes of interest. Some PD patients exhibit downregulation of Ret, the receptor for GDNF and NRTN, which could explain the lack of success seen in the above neurotrophic growth factor gene therapies [45]. Additionally, the degenerative state of the PD brain may affect the transport of growth factors, suggesting that such gene therapies may improve patients receiving therapy earlier in the disease course.

Neural Regeneration

An exciting gene therapy approach tackling PD is generating new neurons through converting astrocytes, abundant in the brain, into induced dopamine-releasing neurons [46][47]. Two teams showed that depletion of PTB, an RNA-binding protein which suppresses neuronal differentiation, using short hairpin RNA (shRNA) [47] or through viral delivery of CasRx, an RNA-targeting CRISPR-Cas, to the brain [46], converted resident astrocytes into neurons and rescued neurochemical and motor deficits in mice [46][47].

2.4. Targeting Disease Genes


As discussed in previous sections, evidence links mutations increasing the expression of α-synuclein to PD and to the formation of Lewy bodies associated with neurodegeneration [48][49][50][51]. It is thus thought that providing neuronal protection could be achieved through downregulating SNCA. Knocking down α-synuclein by shRNA or anti-sense oligonucleotides (ASOs) was reported to prevent neurodegeneration in PD models [52][53][54]. AAV-mediated delivery of shRNA-targeting endogenous SNCA in rats attenuated rotenone-induced progressive motor deficits and neurodegeneration [52]. Furthermore, SNCA downregulation ameliorated neurological deficits in mice models expressing human α-synuclein [53]. Cole et al. (2021) recently showed that ASO-mediated reduction of α-synuclein reversed PD pathology and rescued dopaminergic neuronal function in rodent models of PD [54]. Furthermore, the study reported decreased human α-synuclein levels in the cerebrospinal fluid of non-human primates as a demonstration of the translational potential of the approach [54]. Downregulation of SNCA using CRISPR was also shown to improve cell viability in a PD patient’s iPSC-derived dopaminergic neurons [55]. However, other studies found lowering SNCA levels to be associated with further pathologies in vivo, an issue which is yet to be solved [56][57]. Short interfering RNA (siRNA) delivered into rats’ brains using AAV2/5 vectors to block the translation of α-synuclein in the SNc resulted in even worse motor and behavioral deficits accompanied by reduced TH levels and nigral dopaminergic neurodegeneration [56]. This indicates that both the overexpression and downregulation of SNCA may have a negative effect on neuronal survival, and hints at essential functions of the α-synuclein protein in a healthy brain. It is necessary that alternative strategies tackling α-synuclein are explored. For example, expressing six mutant versions of α-synuclein that block the aggregation of wild-type α-synuclein has shown promising results, but has yet to be validated in vivo [58]. Using CRISPR-interference (dCas9-KRAB), Heman-Ackah et al. (2016) knocked down α-synuclein in iPSCs carrying the SNCA triplication mutation [59]. Another group used an epigenetic approach (dCas9-DNMT3A) by hyper-methylating SNCA’s intron 1 to restore normal mRNA levels in iPSC-derived dopaminergic neurons [55].
LRRK2 mutations cause familial PD or may increase the risk of developing sporadic PD [60]. G2019S and other LRRK2 mutations associated with PD lead to an increased kinase activity, and thus, knocking it out is a sound therapeutic strategy. However, studies have shown that LRRK2 depletion may lead to pathological consequences in other tissues where LRRK2 is expressed, such as the lungs, kidneys and spleen [61][62]. Alternatively, direct intracerebral injections of ASOs depleted LRRK2 protein levels, reduced fibril-induced α-synuclein inclusions and protected TH+ neurons in the brain of mice, with no detected pathological phenotype in other tissues [63]. A Phase I clinical trial using LRRK2 ASO intrathecal injections is currently ongoing in patients with PD (NCT03976349). However, it is essential to employ routes of delivery capable of brain-specific targeting to apply the LRRK2 gene therapy in a less invasive setting.
A potential gene therapy approach for tackling loss-of-function forms of PD is to overexpress the functional protein. A significant proportion of recessive PD is associated with loss-of-function mutations in PRKN and PINK1 genes involved in mitochondrial function and mitophagy [48][64][65][66]. However, since motor symptoms in such forms of PD are efficiently treated by levodopa, it may be unnecessary to develop a gene therapy to restore Parkin function as an alternative treatment.
Mutations in GBA cause Gaucher’s disease, a lysosomal storage disorder, and also represent the most common risk factor for developing PD [67]. A study reported that direct AAV-GBA1 injections in the brains of rodent models of PD reduced α-synuclein levels and pathology [68]. Moreover, intravenous injections of AAV-PHP.B-GBA1 alleviated α-synuclein pathology and produced significant behavioral recovery in A53T mouse models of PD [69]. Intracisternal injection of AAV9-GBA1 to treat PD patients is currently undergoing a Phase I/II clinical trial (NCT04127578).


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