Author: Aneesh Rajput
Mentor: Dr. Nicholas Morano
Lotus Valley International School Noida
Abstract
Parkinson’s disease is a progressive neurodegenerative disorder marked by motor and non-motor symptoms, primarily due to loss of dopaminergic neurons. Gene therapy presents a promising approach to address the molecular mechanisms of this disorder. This paper explores the genetic basis of PD, including monogenic forms involving mutations in the SNCA, LRRK2, VPS35, PINK1, PRKN and GBA genes that contribute to PD pathogenesis. Current gene therapy strategies involve gene delivery to control hyperexcitability of the subthalamic nucleus, restore dopamine biosynthesis, promote neuronal survival via neurotrophic factors and suppress α-synuclein aggregation. The progress of gene therapy procedures in both pre-clinical and clinical settings have been evaluated, demonstrating safety and efficacy in humans and highlighting their potential as gene-modifying targets. However, some challenges such as therapy delivery methods, vector cargo capacity, immune responses and transgene expression longevity still remain. Innovations in regulatory elements, vector design and surgical interventions offer hope for future breakthroughs.
Introduction
Parkinson’s disease (PD) is a chronic, advanced neurodegenerative disorder characterized by a broad spectrum of symptoms. PD affects around 10 million people worldwide, and the prevalence is increasing. It has been nearly 200 years since PD was described and yet the initiating mechanism for this sporadic disease has not been fully elucidated. PD diagnosed by rigidity, bradykinesia, dystonia, postural instability, tremors and gait changes (motor symptoms). Non-motor symptoms include cognitive problems, anxiety, hallucinations and dysphagia. There is an amalgamation of genetic2 and environmental risks3. One of the major environmental risks is aging4. Other risks include familial inheritance, exposure to toxins such as pesticides5, industrial solvents and air pollution, and sex (males are more likely to develop PD)6. The pathophysiology of PD includes aggregation of α-synuclein (for PD with lewy bodies), loss of dopaminergic neurons and hyperexcitable neurons due to various gene changes. Monogenic PD exhibits mendelian inheritance through autosomal dominant mutations in SNCA and VPS35 genes, or recessive mutations in DJ1 and PINK1 genes7.
Many therapeutic interventions have been investigated to treat PD. These include the drug Levodopa8, a precursor to dopamine, which is one of the most effective treatments for managing motor symptoms, anticholinergics, deep brain stimulation9 and various physical therapies.
Here, we will specifically discuss modern gene therapy technologies and their applications for treating PD. Gene therapy is an umbrella term that involves gene editing (modification of an existing gene), gene silencing (suppressing gene expression), gene supplementation (introducing a functional gene) and gene complementation (dysfunctional gene is complemented with a functional copy). While a small percentage of PD cases are directly attributed to specific genetic mutation, gene therapies that target an underlying molecular pathway associated with PD offer the possibility for a wide range of therapeutic strategies 10
Gene therapies under current clinical development for this disorder aim to restore dopamine production, survival of dopaminergic neurons, restore neural excitability, support lysosomal function, deliver growth factors and reduce α-synuclein expression 11.
Genetic Basis of PD
A significant amount of data has shown that risk for PD has a strong genetic basis 12. There are 3 main forms of Parkinson’s: Idiopathic PD is the most common type of the disease. The cause for this type is unknown, but is believed to be both genetic and environmental.
Juvenile PD is a rare form of the disease and refers to parkinsonian symptoms prior to the age of 21, usually due to mutations in parkin, PINK1 and DJ1 genes
Familial PD is inherited due to specific gene mutations. The pattern of inheritance differs based on the gene altered. Different mutations in different genes are linked to development of PD. A lot of them are missense mutations (codon changes by a single nucleotide resulting in a different amino acid at a single position). Other types include nonsense (premature stop codon due to single nucleotide change), frameshift mutations (deletion/insertion of one or multiple nucleotides) and deletions (segment of DNA is missing).
Chromosomal mutations are observed as well. These include duplications (segments of DNA or even an entire chromosome has one or more extra copies) and triplications (a region of chromosome has 3 copies)13.
SNCA mutations
The first discovered genetic cause of PD was a mutation in the SNCA gene, which encodes a neuronal protein called α-synuclein. Pathogenic variants misfold, promoting a structural conversion to crossed β-sheet monomers and leading them to aggregate into structures called Lewy bodies (the pathological trademark of PD)14. Mutations in this gene are rare, with a frequency of 0.045% to 1.1%. They cause autosomal dominant PD. The mutations that cause PD can be missense, duplications or triplications. Individuals with triplications present a rapidly progressive PD with early onset and widespread Lewy body pathology. On the other hand, individuals with duplications resemble the phenotype of idiopathic PD.
The aggregation of α-synuclein is neurotoxic and is accelerated by SNCA pathogenic variants. Impaired mitochondrial respiration, energy deficits and altered lipid metabolism in dopaminergic neurons is also seen.
LRRK2 mutations
LRRK2 encodes the leucine-rich repeat kinase 2 protein which has both kinase and GTPase domains. Pathogenic variants lead to hyperactivation of the kinase domain15.
Missense mutations in this gene were identified as an additional cause of autosomal dominant PD. On an individual level, LRRK2-PD is indistinguishable from idiopathic PD. However, it may display a milder phenotype, such as decreased likelihood of non-motor symptoms. The most common mutation is the p.G2019S mutation, with a prevalence of 1% of PD patients. Different mutations pose different risks of PD and have variable prevalence in different ethnic/regional groups of people, e.g. in Chinese populations the p.G2019S mutation is very rare, however the p.G2385R and p.R1628P variants are common 16.
VPS35 mutations
VPS35 (vacuolar protein sorting 35) encodes a component of the multimeric retromer complex, which mediates trafficking of endosomes. Pathogenic variants cause disruptions in endosomal transport and an unusual aggregation of α-synuclein. There may also be a defect in autophagy and membrane receptor cycling17.
VPS35 mutations are implicated in autosomal dominant PD. The overall prevalence of the only mutation (missense) confirmed, p.D620N, is 0.115% of PD patients. The median onset age is 49 years but the disease progression may be slower than other forms, with less cognitive impairment even after a decade of onset. 18
PINK1 and PRKN mutations
These two genes are considered together because mutations in both cause autosomal recessive PD, and both protein products impact mitochondrial function. 19
PRKN encodes parkin, an E3 ubiquitin ligase involved in the proteasomal degradation system. It also has a role in maintaining DNA integrity. Mutations in PRKN are the most common cause of early onset PD. Slow disease progression and frequent dystonia are characteristic features. A variety of mutations including exonic deletions, duplications, missense and frameshift mutations are described, all of which cause a loss in the function of the PRKN gene20.
PINK1 encodes PTEN-induced kinase 1, a serine/threonine kinase that has a mitochondrial translocation sequence 21. Although relatively rare, PINK1 mutations are the second most common cause of
| GENE | INHERITANCE | FREQUENCY | POPULATION DISTRIBUTION | MUTATIONS | PHENOTYPE | PATHOPHYSIOLOGY |
| SNCA | Autosomal dominant | 0.045% to 1.1% | Mostly Europeans, Asians and Hispanics | Missense, duplications, triplications | Motor fluctuations, cognitive impairment, psychiatric manifestations | Lewy body pathology, impaired respiration and lipid metabolism |
| LRRK2 | Autosomal dominant | Around 1% | Europeans | Missense | Similar to idiopathic PD | LB pathology, hyperactivated kinase domain |
| VPS35 | Autosomal dominant | 0.115% overall | Europeans, Asians, Ashkenazi Jewish | Missense | Similar to idiopathic PD | Impaired autophagy and endosomal transport |
| PRKN | Autosomal recessive | 12.5% of recessive PD | Mostly Asians, Caucasians and Hispanics | Missense, frameshift, structural variants | Early onset PD (EOPD), dystonia | Mitochondrial dysfunction, absence of LB pathology |
| PINK1 | Autosomal recessive | 1.9% of recessive PD | Europeans, Asians, may be frequent in Arab Berber and Polynesians | Missense, nonsense, structural variants | EOPD, movement disorders, dystonia | Mitochondrial dysfunction, lewy bodies may or may not be present |
| GBA | Not strictly mendelian | 5% to 15% | Ashkenazi Jewish, Europeans, Asians, North and South Americans | Missense, complex alleles, structural variants | Similar to idiopathic PD | Impaired autophagic-lysosomal pathway, lipid homeostasis, neuroinflammation, ER stress |
Table-1: Commonly mutated genes in PD
autosomal recessive PD. With a median onset age of 32, the disease is characterized by typical phenotypic features such as bradykinesia, but there is a higher rate of psychiatric manifestations than PRKN mutations. The major type of mutations are missense and nonsense which cause loss of function. These two genes interact within the ubiquitin-proteasome system and maintain mitochondrial quality. Parkin ubiquinates the outer mitochondrial membrane proteins while PINK1 phosphorylates parkin, which helps regulate parkin’s role in mitochondrial stabilization. Pathogenic variants likely disturb the PRKN/PINK1-mediated mitophagy22. Furthermore, mutations in LRRK2 also interfere in this process. 23
GBA mutations
Pathogenic GBA variants, found in 5-15% of PD patients, are the most common genetic risk factor for the disease. This gene encodes glucocerebrosidase (GCase)24. Biallelic variants can cause Gaucher disease (GD), a lysosomal storage disorder. The interest of these mutations as a risk for PD arose when clinicians noticed GD patients develop parkinsonism. Both pathogenic and non-pathogenic variants of GBA are common in PD, with a more aggressive course in terms of dementia and motor development. A recent genetic study about the pathogenic variants of genes that cause lysosomal storage disorders (LSDs) found that more than 50% of the individuals with PD carried variants linked to those genes and there was evidence for burden of damaging alleles associated with risk of PD25. Mutations in the GBA1 gene have attracted the most attention because they are extremely prevalent and increase the risk of PD by 5-30 fold 26.
In contrast to many other genes implicated in monogenic PD, the biological role of GBA is well understood. GCase is a lysosomal hydrolase that breaks down glucosylceramide (GluCer) to ceramide and glucose in the lysosomes. GBA mutants have differential effects on the enzyme’s activity and its trafficking within cells: there is a reciprocal relationship between GCase activity and α-synuclein aggregation, endoplasmic reticulum stress, defective autophagic-lysosomal pathway, dysfunction of lipid homeostasis and neuroinflammation27.
Modern Gene Therapies and their Applications to Parkinson’s
In preclinical studies, researchers have sought to select the best animal model to evaluate PD. Most PD gene therapy studies use 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA) or synucleinopathy, commonly induced in rodents to develop parkinsonian symptoms 28.
Enzyme replacement therapy (ERT) is a widely used gene therapy for PD, in which inactive/absent enzymes are replaced with functional enzyme molecules by injecting the genes that encode them. Substrate reduction therapy (SRT) aims to restore metabolic homeostasis by limiting the amount of substrate synthesized, to a level that can be effectively cleared by the impaired enzyme .
The first step towards an effective gene therapy is engineering a suitable vector. Viruses such as adenovirus and lentivirus are popular as a vector because of their capability of carrying transgenes and delivering them efficiently to target cells29. Each viral vector system comes with its challenges for consideration, which include size of transgene cassette, immunogenicity, cytotoxicity and insertional mutagenesis. In this paper we will discuss about some developing gene therapies targeting various molecular symptoms of PD.
Controlling hyperexcitability
A significant consequence of dopamine loss in basal ganglia, specifically the striatum, is an increase in the excitatory neuronal activity in the subthalamic nucleus. The depolarization pattern of the STN is affected in the form of increased firing frequency (∼30 Hz) along with spike bursts of activity with subsequent hyperpolarization. The excitatory signal affects the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr). Increased activation of GPi and SNr exerts inhibitory effect on the thalamocortical circuits resulting in the classic parkinsonian motor symptoms 30. A gene therapy that uses a recombinant AAV vector system to deliver glutamic acid decarboxylase (GAD) is being explored as an attractive potential therapy31. GAD catalyzes the conversion of glutamate to gamma aminobutyric acid (GABA), an inhibitory neurotransmitter that controls neuronal firing. The therapy consists of a 1:1 ratio of recombinant AAV (rAAV) encoding the two isoforms of GAD cDNA, GAD65 and GAD67. Transgene expression was driven by CMV/CBA promoter and WPRE viral enhancer.
An early study investigating this gene therapy in 6-OHDA parkinsonian rats found it to be both well tolerated and able to diminish parkinsonian motor symptoms. The authors even found the therapy to exert neuroprotective effect on nigral neurons32.
A phase 1 human trial conducted between 2005 and 2007 also demonstrated effectiveness. 12 patients with PD were recruited and divided into 3 groups. They were treated with either a low (1011 vg/ml), medium (3 × 1011 vg/ml) or high dose (1012 vg/ml) of rAAV-GAD via a cannula into the subthalamic nucleus for 1 hour 40 minutes. Significant improvements in motor UPDRS (unified Parkinson’s disease rating scale) scores were observed at 3 months post-surgery and remained evident until 12 months. This led to a phase 2 placebo-controlled trial, with 44 patients having advanced PD. They received bilateral injections of rAAV-GAD in the STN at a vector concentration of 1012 vg/ml via a cannula for 2.5 hours. Six months after delivery motor UPDRS scores improved by 23.1% as compared to patients with sham surgery, which persisted for an year after the surgery 33.
Restoring dopamine production
In PD, the loss of dopaminergic neurons in the substantia nigra is a key characteristic which cause reduced dopamine levels. Dopamine replacement therapy, which uses drugs (e.g. Levodopa) to replenish dopamine levels, is the primary treatment for PD. Levodopa is a precursor to dopamine and can cross the blood brain barrier where it is converted to dopamine by dopa decarboxylase. To prevent peripheral conversion, a dopa decarboxylase inhibitor is typically administered alongside. This inhibitor is unable to cross the BBB, which results in levodopa being converted to dopamine inside the midbrain.
An enticing gene therapy approach to treat dopamine loss is to entirely reconstruct the dopamine synthesis machinery at a specific tissue in the midbrain. In this approach, a lentiviral vector is used to deliver 3 transgenes: tyrosine hydroxylase (TH), GTP cyclohydrolase I (GCH1) and aromatic L-amino acid decarboxylase (AADC). TH converts tyrosine to l-3,4-dihydroxyphenylalanine (l-DOPA), which then gets converted by AADC to dopamine. GCH1 is the rate limiting enzyme in the production of tetrahydrobiopterin, a cofactor of TH 34. ProSavin is a tricistronic lentiviral vector coding TH1, AADC, and GTPCH and was the first lentiviral-based gene therapy vector for a chronic neurodegenerative disorder of the CNS to be tested in humans35.
In another study, the vesicular monoamine transporter (VMAT2) gene was added to TH, GTPCH and AADC to form a four-gene vector in a helper virus-free HSV type 1 vector. This controlled not only dopamine production, but also dopamine release. VMAT2 transports dopamine into synaptic vesicles supporting regulated vesicular release of dopamine, thereby relieving TH from dopamine feedback inhibition 36.
In patients with PD, AADC activity is decreased due to autosomal recessive pathogenic mutants of dopa decarboxylase (DDC) gene, causing defective dopamine synthesis. This depletion of AADC activity could be an important etiology of movement disorders. The overexpression of AADC in rodent37 and non-human primate38 model studies showed therapeutic potential for PD.
A phase 1 human trial in 2019 was conducted to check the safety and tolerability of the AAV-AADC therapy. The study was run by Michael J. Fox Foundation, Voyager Therapeutics, Inc., and Neurocrine Biosciences, Inc. VY-AADC01 consists of recombinant AAV2 capsids carrying the cDNA of the human AADC gene under the control of the cytomegalovirus immediate early promoter. 15 subjects were divided into 3 cohorts and received different concentrations of the treatment: Cohort 1 received 8.3 × 1011vg/ml and up to 450 μl per putamen for a total dose of up to 7.5 × 1011vg; cohort 2 received the same concentration of 8.3 × 1011vg/mL and up to 900 μl per putamen for a total dose of up to 1.5 × 1012vg; and cohort 3 received a higher concentration of 2.6 × 1012vg/ml with the same volume as cohort 2 of up to UPDRS s UPDRS scores were recorded. AADC enzyme activity correlated with treatment dosage increase, improving UPDRS III scores, motor fluctuations and overall quality of life. In general, participants reported improvement in motor functions at 6 months, which increased at later timepoints. Cohorts 2 and 3 showed good improvement in responses at 12 months.
| VECTOR | ANATOMIC TARGET | DELIVERY ROUTE | DOSAGE(S) | PRIMARY OUTCOME MEASURE | CURRENT STATUS |
| AAV-GAD | Subthalamic Nucleus | Intraparenchymal | 1011 vg3 x 1011 vg 1012 vg | Change in UPDRS scores | Completed (NCT00195143) |
| AAV2-GAD | Subthalamic nucleus | Intraparenchymal | 1012 vg | 6 month change from baseline in UPDRS scores | Terminated (NCT00643890) |
| AAV2-AADC (VY-AADC01) | Putamen | Intraparenchymal (MRI guided CED) | 7.5 x 1011 vg1.5 x 1012 vg 4.7 x 1012 vg | Safety of AADC gene transfer | Completed (NCT01973543) |
| AAV2-GDNF | Putamen | Intraparenchymal | 9 x 1011 vg3 x 1011 vg9 x 1011 vg3 x 1012 vg | Safety and tolerability | Completed (NCT01621581) |
| AAV2-GDNF | Putamen | Intraputaminal | Not disclosed | Safety and tolerability | Ongoing (NCT06285643) |
| AAV2-NTRN (CERE-120) | Putamen | Intraputaminal | 1.3 x 1011 vg5.4 x 1011 vg | Safety and tolerability | Completed (NCT00252850) |
| AAV2-NTRN(CERE-120) | Putamen | Intraputaminal | 5.4 x 1011 vg | Change in UPDRS scores | Completed(NCT00400634) |
| AAV2-NTRN(CERE-120) | Putamen, Substantia Nigra | Intraparenchymal | 2.4 x 1011 vg (SN)1012 vg (putamen) | Changes in UPDRS scores | Completed (NCT00985517) |
| AAV-GBA1 (PR001/ LY3884961) | General | Intracisternal | Not disclosed(2 cohorts) | Safety and tolerability | Ongoing (NCT04127578) |
| AAV-GBA1 (PR001/ LY3884961) | General | Intravenous | Not disclosed(3 cohorts) | Safety and tolerability | Ongoing (NCT05487599) |
| AAV-GBA1 (PR001/ LY3884961) | General | Intracisternal | Not disclosed | Safety and tolerability | Ongoing (NCT04411654) |
Table-2: Clinical trials for PD gene therapy
Delivering neurotrophic factors
Naturally occurring proteins that support the growth, differentiation, functioning, survival and synaptic plasticity of neurons are called trophic factors. Some trophic factors have the potential to protect or regenerate progressively damaged dopaminergic neurons in PD patients. Particular focus has been placed on the glial cell-line derived neurotrophic factor family of ligands (GFL) that encompass glial cell-line derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN). The GFL signals by activating the RET receptor complex with the GDNF family receptor α (GFRα), initiating the MAP kinase and PI3-kinase pathways that promote neuronal survival and neuritogenesis. Activation of GFRα also activates transcription factors Nurr1 and Pitx3 which are crucial for the activation of the gene which induces expression of AADC.
GDNF is a potent factor associated with survival and regeneration, along with maintenance of dopaminergic neurons. Several clinical trials have assessed the intraputaminal infusion of GDNF 40. One was a phase 1 safety study of AAV2-GDNF infused via CED into bilateral putamina of adult patients with PD. Four escalating dose levels were administered to 6 patients per cohort: 9 × 1010vg, 3 × 1011vg, 9 × 1011vg and 3 x 1012 vg. For each outcome measure, a repeated-measures analysis of variance (RM-ANOVA) examined the effect of time on [18F]FDOPA (fluorinated L-dopa) values, UPDRS score, and TLED (total levodopa equivalent doses). Increased FDOPA uptake was recorded with increase in concentration, indicating GDNF expression. However, no statistically significant changes in UPDRS scores were observed between dose cohorts 41. A phase 2 study began in mid-2024 where moderately affected PD patients received the same gene therapy, the results of which are yet to be published.
NRTN is another important trophic factor known to exert protective effect on dopaminergic midbrain neurons. It uses roughly the same molecular pathway as GDNF. A phase 1 trial of PD patients receiving bilateral intraputaminal injections of AAV2–NTRN (CERE-120) was conducted. Individuals received dosage in two groups: 1.3 × 1011 and 5.4 × 1011 vg, and it was found to be safe and well tolerated. However, it did not change UPDRS scores after 12 months 42. A subsequent phase 2 study to evaluate the safety and efficacy of AAV2–NRTN in a double-blind randomized trial with 34 patients were enrolled who received 40 μL per hemisphere of AAV2-NTRN (5.4 × 1011 vg/mL). This cohort, however, did not experience clinically significant improvements compared to a placebo group, at 12 months following the infusion43. A long-term and postmortem analysis of patients who received the therapy for 10 years revealed that although transgene expression could persist long term, it did not produce clinical improvements. Investigators hypothesized the lack of efficiency to be a result of failure of retrograde transport of the vector from putamen to substantia nigra. Another phase-1 study was conducted, where CERE-120 was bilaterally delivered to 6 subjects in two dosage groups, to both the substantia nigra (SN) and the putamen. The procedure was well-tolerated, with no adverse effects over the two year follow up44.
GBA1 Delivery
Substantial evidence highlights the importance of lysosomal mechanisms in PD pathogenesis and susceptibility. The GBA gene encodes for GCase, deficiency of which causes accumulation of GluCer and other glycolipids, leading to neuroinflammation and toxicity. GCase has also been hypothesized to impact α-synuclein aggregation. Therefore, a viable gene therapy strategy would be to increase GCase activity to enhance the functioning of lysosomes and limit the aggregation of α-synuclein. This is supported by several studies utilizing experimental mouse models of PD. They have demonstrated that restoring GCase activity through viral-mediated delivery of GBA1 is sufficient to rescue α-synuclein pathology, reduce neuroinflammation and gliosis, and prevent cognitive and motor deficits. The delivery of GBA1 cDNA in the AAV9-PHP.B vector (GBA1-P2A-GFP) was sufficient to prevent the formation of insoluble α-synuclein deposits across multiple brain regions in a A53T-SNCA transgenic mouse model of PD45.
Patients with GBA1-PD often exhibit a more aggressive disease phenotype, requiring more intensive treatment strategies to counteract poor prognosis. ERT and SRT are being studied as effective approaches. The major roadblock with them is that the recombinant forms of GCase cannot penetrate through the BBB. AAV-GBA1 delivery directly into the midbrain circumvents the problems with the BBB and the short half-life of recombinant enzymes.
Based on these promising preclinical studies, 3 clinical trials, sponsored by Prevail Therapeutics, were conducted. Although all 3 use the same gene therapy, only one of these involves patients with PD. First is the PROPEL study, a phase 1/2a trial of PR001(aav9 recombinant vector) on individuals who carried at least one GBA mutation. It began in 2020 with 20 individuals split into high and low dose groups (dosage not disclosed), and PR001 was administered by intracisternal injection. During the first year, patients will be evaluated for the effect of PR001 on safety, tolerability, immunogenicity, biomarkers, and clinical efficacy measures. Patients will continue to be followed for an additional 4 years to continue to monitor safety as well as selected biomarker and efficacy measures. PROVIDE is a phase 1/2 study to evaluate a single intravenous dose of PR001 in infants with type-2 GD that started in 2021. PROCEED is a phase 1/2 study to evaluate a single intravenous dose of PR001 in patients with peripheral manifestations of GD that started in 2022. All three studies are currently ongoing, with results expected to be released by 2028 for PROVIDE, 2029 for PROPEL and 2030 for PROCEED trial.
Considerations for Future Research and Treatment
Despite decades of research, two main problems persist in this field. The first is the difficulty in delivering the vector system to the target tissue, and the second is inadequate expression of the transgene and small size of the transgene cassette.
Promoters in the transgene cassettes should be optimized for specific needs such as tissue type and level of expression. The specificity of transgene expression within the targeted tissues is crucial in order to achieve sufficient transduction efficiency with low dosing and to minimize off-target effects. Additional regulatory elements such as enhancers can be engineered to improve expression activity and specificity46.
Riboswitches are non-coding RNAs that can bind specific metabolites and control gene expression47. Using them over other regulatory systems has the advantages of being compatible with FDA-approved drugs, negligible immunogenicity and short length of the sequences, which is particularly useful when combined with the limited packaging capacity of rAAVs, making it a powerful system for regulating rAAV-based gene therapy48.
Although AAV has a lower immunogenicity than other viruses, it has been reported that it can trigger pre-existing immunity, innate immunity, and adaptive immune responses against the vector49. These reactions can hinder therapeutic effectiveness in clinical applications. A potential solution to suppress AAV-neutralizing antibodies is to introduce bacterial endopeptidases such as imlifidase (IdeS) concurrent with drug administration that degrade circulating immunoglobin G (IgG) molecules, and thus allow better vector transduction50. Another strategy to counter AAV antibody response is to block toll-like receptor 9 (TLR9), an immune sensor of DNA, through the administration of specific single stranded DNA oligonucleotides (termed “TLR9i”). TLR9i sequences can be directly incorporated into the vector genome to dampen immune responses51. Furthermore, many gene therapy trials use a triple immune suppression regimen that includes steroids, rituximab, and rapamycin.
The cargo capacity of the virus is another topic of consideration, as many strains demonstrate very limited transgene capacity. The small size of AAV for example, allows only about 4.7 kilobases of foreign DNA to be packaged, which is a major drawback52. The HSV-1 amplicon system provides an opportunity to address this, with the potential to deliver transgenes of up to 150 kb. This uniquely large cargo capacity has been shown to support the delivery of large genomic DNA sequences expressing neurological disease genes53. HSV-amplicon-based delivery of a Parkinson’s gene into the nigrostriatal system has shown to work effectively in mice, suggesting that such an approach could be used for delivering an entire locus to correct a mutation of PD genes 54.
Treatment administration still remains one of the greatest challenges to effectively deliver a gene therapy. Most clinical trials use a cannula to directly deliver the viral vector to the targeted brain tissue, however the technology and rates of infusion vary across studies. Intraparenchymal, intravenous, intracerebroventricular and intrathecal delivery are some approaches for transducing the CNS55. Direct intraparenchymal delivery into the brain is an effective way to reduce the dose/volume of AAV required and thereby alleviates concerns regarding off-target delivery and extra-cranial side effects56. A pre-clinical approach to improve this method is to utilise focused ultrasound to increase the permeability of the BBB within the target tissue, in company with peripheral vascular delivery of the rAAV within microbubbles57. Rodent studies with this technique have shown good biodistribution within targeted brain regions.
Gene therapy with optogenetics58 or chemogenetics59 could also prove to be a viable alternative to treating PD because they provide a more specific intervention than deep brain stimulation (DBS) or ablation. Editing the genome with CRISPR-CAS9 technology60 61might be another successful upcoming form of personalized gene therapy.
As the field of gene therapy progresses, new genetic targets and gene editing technology would evolve. More therapies for neurodegenerative diseases would emerge, which target successful delivery and sustained gene expression. Furthermore, the role of neurosurgeons may be key in developing surgeries to this complex problem. In conclusion, while challenges remain prevalent in this field, encouraging studies, pre-clinical and clinical trials suggest that we can remain optimistic about the future of gene therapy for PD.
Abbreviations
PD Parkinson’s disease
LRRK2 Leucine-rich repeat kinase
VPS35 Vacuolar protein sorting
PRKN Parkin
PINK1 PTEN-induced kinase
LB Lewy Body
EOPD Early onset PD
ER Endoplasmic reticulum
GCase Glucocerebrosidase
GD Gaucher disease
GluCer Glucosylceramide
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
6-OHDA 6-hydroxydopamine
ERT Enzyme replacement therapy
SRT Substrate reduction therapy
STN Subthalamic nucleus
SNr Substantia nigra pars reticulata
SN Substantia nigra
GPi Internal globus pallidus
GAD Glutamic acid decarboxylase
GABA Gamma aminobutyric acid
rAAV Recombinant adeno associated virus
CMV/CBA Cytomegalovirus/Chicken β-actin
WPRE Woodchuck hepatitis virus post-transcriptional regulatory element
UPDRS Unified parkinson’s disease rating scale
BBB Blood brain barrier
TH Tyrosine hydroxylase
AADC Aromatic L-amino acid decarboxylase
GTPCH GTP cyclohydroxylase I
CNS Central nervous system
l-DOPA l-3,4-dihydroxyphenylalanine
VMAT2 Vesicular monoamine transporter
DDC Dopa decarboxylase
MRI Magnetic resonance imaging
CED Convection enhanced delivery
GFL Glial cell-line derived neurotrophic factor family of ligands
GDNF Glial cell-line derived neurotrophic factor
NRTN Neurturin
ARTN Artemin
PSPN Persephin
GFRα GDNF family receptor α
RM-ANOVA Repeated measures.analysis of varianc
FDOPA Fluorinated L-dopa
TLED Total levodopa equivalent doses
IdeS Imlifidase
IgG Immunoglobin G
TLR9i Toll-like receptor 9 inhibitory
HSV-1 Herpes simplex virus 1
vg Vector genome
kb Kilobase
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About the author
Aneesh Rajput
Aneesh is currently studying in grade 12 at Lotus Valley Noida. In the past two years he has developed a strong passion for molecular biology and has decided to pursue it as a career. Although Aneesh has worked on projects related to the field before, this is his very first research paper. He is also a core member of a band, Music Factory, and actively participates in a plethora of social service events. Apart from this, he likes to write and sketch during his leisure time.