Key result
Vector-mediated genetic silencing of striatal CaV1.3 completely prevented and ameliorated levodopa-induced dyskinesias in severely parkinsonian rats while preserving the motoric benefits of levodopa.
Why the study?
Uniformly effective and well-tolerated antidyskinetic treatment for levodopa-induced dyskinesias in Parkinson's disease remains an unmet need, and clinically available CaV1.3-inhibiting drugs lack adequate potency.
Does genetic silencing of striatal CaV1.3 prevent or ameliorate levodopa-induced dyskinesias in severely parkinsonian rats?
Does genetic silencing of striatal CaV1.3 prevent or ameliorate levodopa-induced dyskinesias in severely parkinsonian rats?
Genetic silencing of striatal CaV1.3 channels prevents and ameliorates levodopa-induced dyskinesias in parkinsonian rats without compromising the motor benefits of levodopa.
BACKGROUND: Levodopa-induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well-tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa-induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa-induced dyskinesias. METHODS: To provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high-potency, target-selective, mRNA-level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa-induced dyskinesias in severely parkinsonian rats. RESULTS: We demonstrate that vector-mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa-induced dyskinesias, and this antidyskinetic benefit persists long term and with high-dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa-induced dyskinesias. Importantly, motoric responses to low-dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability. DISCUSSION: The current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa-induced dyskinesia side effect.
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Steece‐Collier et al. (2019) studied Levodopa-induced dyskinesias in Parkinson's disease. CaV1.3 shRNA (vector-mediated silencing of striatal CaV1.3 expression) was evaluated on Induction and severity of levodopa-induced dyskinesias. Vector-mediated genetic silencing of striatal CaV1.3 completely prevented and ameliorated levodopa-induced dyskinesias in severely parkinsonian rats while preserving the motoric benefits of levodopa.
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