# Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $590,058

## Abstract

Project Summary
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 naïve 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.

## Key facts

- **NIH application ID:** 9975239
- **Project number:** 5R01NS110398-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Jeffrey H Kordower
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $590,058
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975239

## Citation

> US National Institutes of Health, RePORTER application 9975239, Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD (5R01NS110398-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9975239. Licensed CC0.

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