One often debilitating side-effect of standard pharmacotherapy for Parkinson's disease (PD), levodopa administration, are unwanted involuntary movements known as levodopa-induced dyskinesia (LID). Eliminating LID remains a significant unmet need in PD therapy. There are currently no FDA approved drug treatments for LID, yet up to 90% of individuals with PD develop this side-effect. The L-type calcium channel CaV1.3 is a target of interest for LID prevention. Loss of striatal dopamine (DA) in PD results in dysregulation and overactivity of striatal CaV1.3 channels leading to synaptic pathology, including the loss of dendritic spines on striatal spiny projection neurons that appears to be involved in LID. While initial studies delivering pharmacological CaV1.3 channel antagonists reduced LID dose-dependently, the effects were partial and transient, with potential liability for cardiovascular side-effects due to the lack of specificity of existing drugs for the CaV1.3 channel. To provide unequivocal target validation, free of pharmacological limitations, we developed a rAAV-CaV1.3-shRNA to provide continuous, high potency, target-selective, mRNA-level silencing of striatal CaV1.3 channels. We examined whether genetic silencing of these dysregulated calcium channels could prevent LID induction in previously levodopa nave parkinsonian rats and/or whether it could reverse these abnormal behaviors in parkinsonian rats already expressing a severe LID phenotype. In our `LID prevention studies' we found that gene level silencing of striatal CaV1.3 channels in severely parkinsonian rats, prior to the introduction of levodopa provides uniform and complete protection against the induction of LID, and that the antidyskinetic benefit is sustained over time even with high doses of daily levodopa. In our `LID reversal studies' we observed that rAAV-mediated CaV1.3 silencing in parkinsonian rats with already established LID could ameliorate these behaviors, with a one-week drug withdrawal 'drug holiday' appearing to be beneficial and/or necessary. Importantly this approach did NOT interfere with motor benefit of levodopa and showed a tendency to enhance motoric response to low dose levodopa. Gene delivery resulting in striatal CaV1.3 silencing provides some of the most profound antidyskinetic benefit reported to date. If these findings can be translated into a clinical application with a similar magnitude, this would provide a much-needed breakthrough in treatment of individuals with PD and would allow the most powerful antiparkinsonian therapy ever identified to work unabated through the duration of the disease. In the current application we propose a series of translational studies in rats and nonhuman primates that will allow us to expand upon these initial proof-of-principle studies and test specific hypotheses of safety and efficacy that will be required for the clinical development of genetic silencing of striatal CaV1.3 channels for LID.

Public Health Relevance

One often debilitating side-effect of standard pharmacotherapy for Parkinson's disease is levodopa-induced dyskinesia (LID), which remains an unmet medical need. Overactivity of L-type calcium channels, CaV1.3, on striatal neurons has been linked to LID but existing antagonist drugs lack of specificity and potency for this channel with preclinical data indicating that these compounds suppress LID only partially and transiently. For validation of the CaV1.3 channel as a target for anti-LID therapy, in this proposal we extend our recent work demonstrating that selective silencing of striatal CaV1.3 channels with a gene therapy approach in rats provides dramatic efficacy in preventing LID development, as well as reversing pre-existing LID.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Michigan State University
Schools of Medicine
East Lansing
United States
Zip Code