Gene Therapy Approaches for Parkinson's Disease

Author: Sanne Zwikker¹

¹Department of Biology, University of Rochester, Rochester NY, USA

szwikker@u.rochester.edu

Introduction

Parkinson’s Disease (PD) is a progressive neurodegenerative disease of the nervous system, characterized by the loss of dopaminergic neurons in the substantia nigra of the brain. This neuronal degeneration leads to hallmark motor symptoms, including muscle tremors, rigidity of the limbs and torso, and slowness of movement (bradykinesia). PD has become increasingly more prevalent in today’s society, affecting 1% of the population aged over 65 years and 4% of the population aged over 85 years (Salles et al. 2024). This paper will focus on the genetic and environmental causes of PD, a most recent clinical gene therapy trial, a possible new gene therapy to combat the development and symptoms of PD, and possible ethical concerns that arise with the newly developed gene therapy.

Genetic mutations and development of PD

PD develops through an accumulation of both genetic and environmental factors. Only 13% of people with PD have a known genetic link (Deng et al. 2018). Roughly 5-10% of individuals with PD have a monogenic form of the disease with Mendelian Inheritance caused by the mutation of a single gene such as SNCA, PARK2, PARK7, PINK1, and LRRK2 (Klein and Westenberger 2012). The SNCA gene is responsible for the production of the protein alpha-synuclein. When mutated the translated protein clumps together in what is called Lewy bodies, causing progressive neuronal death through mitochondrial impairment. Mutation and duplications of the SNCA gene cause an autosomal dominant form of PD (Oliver Day and Mullin 2021). PARK2, PARK7, and PINK1 are oftentimes considered together since their protein products are linked to mitochondrial function, which when mutated, cause autosomal recessive forms of PD (Oliver Day and Mullin 2021). LRRK2 also produces a protein kinase that when mutated are linked to late-onset PD. Mutations in the LRRK2 gene cause an autosomal dominant form of PD (Johns Hopkins Medicine 2025).

Environmental factors can also affect an individual’s ability to develop PD. Studies have been performed to conclude the use of pesticides and chemical exposures leads to a higher risk of developing PD, with one study even arguing that PD is predominantly an environmental disease (Dorsey and Bloem 2024). The use of pesticides has been found to correlate to PD diagnosis. Use of pesticides such as rotenone and paraquat has proven to cause mitochondrial dysfunction, leading to the eventual development of PD (Dorsey and Bloem 2024).

Clinical Gene Therapy Trial

In a 2020 phase I clinical trial, Aromatic L-Amino Acid Decarboxylase Gene Therapy was used to enhance the performance of levodopa in PD (Nutt et al. 2020). Synthesis levodopa is done by the L-amino acid decarboxylase (AADC). With disease progression, AADC levels fall resulting in previous dosages of levodopa being ineffective and an increased dosage of levodopa being necessary. To combat this, AADC enzymatic activity was replaced with adeno-associated viral vector serotype-2 (AAV2). AAV2s containing complementary DNA for the AADC enzyme was infuse into the putamen of the brain via neurosurgical delivery.

This clinical trial focused on the surgical administration of VY-AADC01, a gene therapy developed by Voyager Therapeutics. This is an AAV2 vector for the delivery of the gene encoding the AADC enzyme. The results showed VY-AADC01 was well tolerated and lead to an increase in AADC enzyme activity. Enzymatic activity was monitored through ¹⁸F-fluoro-L-dihydroxyphenylalanine positron emission tomography, confirming an increase in AADC enzymatic activity. Further they tracked motor scores over time after gene therapy and levodopa infusion and averaged six measurements taken at -1 hour, -0.5 hour, and 0 hour on two separate pre-treatment days. They then truncated values to offset the values when levodopa wore off causing below baseline values. It was noted the gene therapy augmented the response to low-dose levodopa infusions, meaning efficacy in dopamine levels can be reached at lower levodopa doses.

My developed gene therapy

In PD, accumulation of alpha-synuclein is caused by mutations in the SNCA gene. Alpha-synuclein is central in the further development of both spontaneous and inherited PD. It is possible that reduction of overproduced alpha-synuclein can result in the slowing of disease progression and possible relief from symptoms. This can be achieved through the use of RNA interference (RNAi). RNAi is already an existing natural eukaryotic cellular process where small, double-stranded RNA molecules (siRNAs) silence gene expression.

The process of RNAi involves a double stranded RNA (dsRNA). An enzyme called Dicer cuts the dsRNA into the smaller siRNA fragments. When the siRNA fragments are incorporated into the RNA-induced silencing complex (RISC), one strand of the siRNA is used as a guide to find and bind to a complementary mRNA molecule. Once the target mRNA is found, the RISC complex cleaves the sequence and thus silencing the expression of that specific gene.

In application to PD, siRNAs can be used to silence the gene expression of alpha-synuclein to reduce high levels of alpha-synuclein. The primary endpoints for this study would be to assess improvement of PD-like symptoms through a Unified Parkinson’s Disease Rating Scale (UPDRS) motor score in which finger-tapping speeds would be tested to determine if bradykinesia scores change. The patient group identified in the clinical trials would be adults diagnosed with late-onset Parkinson’s Disease.

Ethical Concerns

In my designed clinical trial, there are some ethical concerns that must be addressed. Challenges with off-target effects and safe delivery methods may bring harm to the patients. siRNAs have the potential to silence unintended genes, or have prolonged, unintended activity on the correct target gene. This may cause serious health complications to the patients receiving such treatment. Ethical delivery methods must also be discussed since administering the siRNAs to the patient involves bypassing the blood-brain barrier to deliver the siRNAs to the brain. This can lead to invasive injections into the cerebral ventricles of the brain to bypass this barrier. This raises ethical concerns in respect of patient autonomy and long-term consequences after treatment.

Conclusion

Parkinson’s Disease is a neurodegenerative disease that develops through the accumulation of genetic and environmental factors. In this paper, we discussed the key genes that when mutated, lead to the production of misfolded proteins and progress PD symptoms. We also discussed the correlation between environmental factors such as pesticides to progression of PD. We then focused on the clinical gene therapy trial of Aromatic L-Amino Acid Decarboxylase Gene Therapy. Based on the information known about PD and having seen other possibilities with gene therapy in PD, an original gene therapy was designed. This designed gene therapy utilizes RNAi to silence the expression of the mutated SNCA gene, leading to a reduction in alpha-synuclein production and thus a slowing in PD progression. Lastly, the ethical concerns of this designed gene therapy were addressed, raising awareness and concern for respect of patient autonomy when performing such gene therapies that may require invasive implantation procedures.

Bibliography

Day JO, Mullin S. 2021. The Genetics of Parkinson’s Disease and Implications for Clinical Practice. Genes. 12(7):1006.

Deng H, Wang P, Jankovic J. 2018. The genetics of Parkinson disease. Ageing Research Reviews. 42:72–85. doi:https://doi.org/10.1016/j.arr.2017.12.007. https://www.sciencedirect.com/science/article/pii/S1568163717302453.

Dorsey ER, Bloem BR. 2024. Parkinson’s Disease Is Predominantly an Environmental Disease. Journal of Parkinson’s Disease. Preprint(Preprint):1–15. doi:https://doi.org/10.3233/JPD-230357. https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd230357.

John Hopkins Medicine. 2025. The Genetic Link to Parkinson’s Disease. wwwhopkinsmedicineorg. https://www.hopkinsmedicine.org/health/conditions-and-diseases/parkinsons-disease/the-genetic-link-to-parkinsons-disease.

Klein C, Westenberger A. 2012. Genetics of Parkinson’s Disease. Cold Spring Harbor Perspectives in Medicine. 2(1):a008888–a008888. doi:https://doi.org/10.1101/cshperspect.a008888. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253033/.

Nutt JG, Curtze C, Hiller A, Anderson S, Larson PS, Van Laar AD, Richardson RM, Thompson ME, Sedkov A, Leinonen M, et al. 2020. Aromatic L‐Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson’s Disease. Movement Disorders. 35(5):851–858. doi:https://doi.org/10.1002/mds.27993.

Salles PA, José Miguel Tirapegui, Chaná-Cuevas P. 2024. Genetics of Parkinson’s disease: Dominant forms and GBA. Neurology perspectives. 4(3):100153–100153. doi:https://doi.org/10.1016/j.neurop.2024.100153.