Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting in loss of dopamine producing neurons causing tremor, rigidity, and bradykinesia. As current pharmacological therapies are unable to prevent progression, gene therapy is currently being investigated as an alternative approach. Current targets include: GDNF, BDNF, CDNF, VEGF, alpha synuclein, AADC, and GAD. This review article explores the various gene therapy targets currently being studied for the treatment of PD.

 

Methods: All the data collected, reviewed, and discussed were collected using published peer-reviewed journal articles from PubMed. The information provided in this review was not limited to a specific time frame.

 

Results: Neurotrophic factor-based gene therapy using glial derived neurotrophic factor (GDNF), brain derived neurotrophic growth factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) have regenerative and protective effects on dopaminergic neurons in the CNS. Preclinical trials determined that GDNF provided regrowth of striatal neurons and improvement of functional symptoms, while phase 1 clinical trials have failed to do so. In phase 1 clinical trials, AAV2-AADC delivery was well-tolerated and demonstrated visible improvements in PD symptoms and restoration of dopaminergic pathway. When treated with AAV-VEGF transduction, dysregulated movements were decreased. Overexpression of Abl, fractalkine, and heat shock proteins are proven to prevent the aggregation of alpha synuclein through degradation of alpha synuclein and protect tyrosine hydroxylase neurons. Phase 1 and 2 clinical trials show that GAD treatment in PD patients was able to provide a well-tolerated long-term benefit. 

 

Discussion: The above-mentioned gene targets play an important role in synthesis of dopamine, regulation of dopamine production, or modulation of the dopaminergic neuronal pathway; thus, demonstrate great potential as targets for modulating PD physiological and neuropathological symptoms. Upon viral vector transduction, dopamine production, synaptic connections, and motor function improved relative to control groups. 

 

Conclusion: Gene therapy as a treatment modality for PD is growing as data from in vivo and clinical studies show efficacy and safety; however, clinical trials are currently underway to further evaluate these aspects. Further research to assess the long-term benefits, consequences, and effectiveness of PD gene therapy in halting the progression of PD pathology and physiology are required.

 

References:

GDNF: 

1. Ayanlaja, A.A., et al., The reversible effects of glial cell line-derived neurotrophic factor (GDNF) in the human brain. Semin Cancer Biol, 2018. 53: p. 212-222.
2. Grondin, R., et al., GDNF revisited: A novel mammalian cell-derived variant form of GDNF increases dopamine turnover and improves brain biodistribution. Neuropharmacology, 2019. 147: p. 28-36.
3. Lapchak, P.A., et al., Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson’s disease. Brain Res, 1997. 777(1-2): p. 153-60.
4. Du, Y., et al., Adeno-associated virus type 2 vector-mediated glial cell line-derived neurotrophic factor gene transfer induces neuroprotection and neuroregeneration in a ubiquitin-proteasome system impairment animal model of Parkinson’s disease. Neurodegener Dis, 2013. 11(3): p. 113-28.

BDNF: 

1. Binder, D.K. and H.E. Scharfman, Brain-derived neurotrophic factor. Growth Factors, 2004. 22(3): p. 123-31.
2. Hernandez-Chan, N.G., et al., Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson’s disease. J Biomed Sci, 2015. 22(1): p. 59.
3. Klein, R.L., et al., Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res, 1999. 847(2): p. 314-20.
4. Sun, M., et al., Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson’s disease. Brain Res, 2005. 1052(2): p. 119-29.

CDNF: 

1. Bäck, Susanne, et al. “Gene Therapy with AAV2-CDNF Provides Functional Benefits in a Rat Model of Parkinson’s Disease.” Brain and Behavior, vol. 3, no. 2, 2013, pp. 75–88., https://doi.org/10.1002/brb3.117. 
2. Axelsen, Tobias M., and David P.D. Woldbye. “Gene Therapy for Parkinson’s Disease, an Update.” Journal of Parkinson’s Disease, vol. 8, no. 2, 2018, pp. 195–215., https://doi.org/10.3233/jpd-181331. 
3. Barker, Roger A., et al. “GDNF and Parkinson’s Disease: Where next? A Summary from a Recent Workshop.” Journal of Parkinson’s Disease, vol. 10, no. 3, 2020, pp. 875–891., https://doi.org/10.3233/jpd-202004. 
4. Bondarenko, Olesja, and Mart Saarma. “Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain.” Frontiers in Cellular Neuroscience, vol. 15, 2021, https://doi.org/10.3389/fncel.2021.682597.

VEGF: 

1. Xiong, N, et al. “VEGF-Expressing Human Umbilical Cord Mesenchymal Stem Cells, an Improved Therapy Strategy for Parkinson’s Disease.” Gene Therapy, vol. 18, no. 4, 2010, pp. 394–402., https://doi.org/10.1038/gt.2010.152. 
2. Falk, Torsten, et al. “Vascular Endothelial Growth Factor B (VEGF-B) Is up-Regulated and Exogenous VEGF-B Is Neuroprotective in a Culture Model of Parkinson’s Disease.” Molecular Neurodegeneration, vol. 4, no. 1, 2009, p. 49., https://doi.org/10.1186/1750-1326-4-49. 
3. Tian, You-yong, et al. “Favorable Effects of VEGF Gene Transfer on a Rat Model of Parkinson Disease Using Adeno-Associated Viral Vectors.” Neuroscience Letters, vol. 421, no. 3, 2007, pp. 239–244., https://doi.org/10.1016/j.neulet.2007.05.033.

 

GAD: 

1. Blits, Bas, and Harald Petry. “Perspective on the Road toward Gene Therapy for Parkinson’s Disease.” Frontiers in Neuroanatomy, Frontiers Media S.A., 9 Jan. 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220060/. 
2. Axelsen, Tobias M, and David P D Woldbye. “Gene Therapy for Parkinson’s Disease, an Update.” Journal of Parkinson’s Disease, IOS Press, 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027861/. 
3. Emborg, Marina E, et al. “Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism.” Journal of Cerebral Blood Flow & Metabolism, 2007. 
4. Niethammer, Martin. “Long-Term Follow-Up of a Randomized AAV2-GAD Gene Therapy Trial for Parkinson’s Disease.” JCI Insight, 6 Apr. 2017. 

AADC:

1. Ciesielska, Agnieszka, et al. “Depletion of AADC Activity in Caudate Nucleus and Putamen of Parkinson’s Disease Patients; Implications for Ongoing AAV2-AADC Gene Therapy Trial.” PloS One, Public Library of Science, 6 Feb. 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293261
2. Christine, Chadwick W, et al. “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease.” Annals of Neurology, John Wiley & Sons, Inc., May 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593762/. 
3. Mittermeyer, Gabriele, et al. “Long-Term Evaluation of a Phase 1 Study of AADC Gene Therapy for Parkinson’s Disease.” Human Gene Therapy, Mary Ann Liebert, Inc., Apr. 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530392/. 

Alpha synuclein: 

1. Henderson, M.X., J.Q. Trojanowski, and V.M. Lee, α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies. Neurosci Lett, 2019. 709: p. 134316.
2. Mullin, S., et al., Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol, 2020. 77(4): p. 427-434.
3. Migdalska-Richards, A., et al., Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann Neurol, 2016. 80(5): p. 766-775.
4. Migdalska-Richards, A., et al., Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse, 2017. 71(7).