Nova Southeastern College of Osteopathic Medicine Davie, Florida, United States
Background and Hypothesis: Parkinson’s disease (PD), a chronic progressive neurodegenerative disorder that results in loss of dopamine producing neurons causing tremor, rigidity, and bradykinesia. Gene therapy poses an alternative treatment option for PD as current pharmacologic therapy is unable to halt disease progression. In this study, we investigated the relationship between current gene therapy targets-GDNF, BDNF, CDNF, VEGF, alpha synuclein, AADC, and GAD- and their treatment efficacy in PD. This topic is important because it allows clinicians/medical students to gain not only a better understanding of disease pathophysiology but also brings to light an upcoming novel approach to treat one of the most common neurologic disorders. By filling in knowledge gaps about PD, this study hopes to educate, inform, and highlight the novel therapies that are currently in development. We aim to provide current/future medical practitioners the tools needed to target this multifactorial disease.
Methods: In this review article, 159 published peer-reviewed PubMed journal articles were collected, reviewed, and discussed. The keywords utilized for this search included "Parkinson’s Disease + Gene Therapy", "BDNF + Gene Therapy + Parkinson’s Disease", "GDNF + Gene Therapy + Parkinson’s Disease", "CDNF + Gene Therapy + Parkinson’s Disease", "VEGF + Gene Therapy + Parkinson’s Disease", “alpha synuclein + Gene Therapy + Parkinson’s Disease", "AADC + Gene Therapy + Parkinson’s Disease", and "GAD + Gene Therapy + Parkinson’s Disease". The information provided in this review was not limited to a specific time frame.
Results: Based on the findings of this study neurotrophic factor based gene therapy-GDNF, BDNF, and CDNF- showed regenerative and protective effects on dopaminergic neurons in the CNS. Furthermore, preclinical trials utilizing GDNF showed regrowth of striatal neurons and improvement of functional symptoms. Additionally, phase 1 clinical trials of AADC gene therapy vector were not only well tolerated but also demonstrated visible improvements in PD symptoms and restoration of dopaminergic pathway. Preclinical trials of VEGF showed a reduction in dysregulated movements as measured by the UPRDS score. 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. Lastly, GAD phase 1 and 2 clinical trials have shown well-tolerated, long-term patient benefit through modulation of subthalamic nucleus (STN) overactivity.
Conclusion: The gene therapy targets mentioned above show the potential to improve PD patients’ neuropathological symptoms either through improvements in the synthesis of dopamine, regulation of dopamine production, or modulation of the dopaminergic neuronal pathway. This studies efficacy is medically and clinically significant because it allows students and practitioners to gain a more holistic understanding of PD and remain up-to-date on future treatment modalities. By exploring and learning about alternative treatment approaches, a multi-systematic approach can be used to potentially offer patients an alternative treatment option and the patient-centered holistic treatment that PD therapy requires. Further research to assess long-term benefits, consequences, and effectiveness are required.
Acknowledgement of Research Study Sponsors and IRB: Based on the method of our research, which is a review article, the need for an IRB statement was reviewed but was later determined to be exempt.
