Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia

Abstract

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. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

“…In recent work we demonstrated that genetic silencing of striatal Cav1.3 L-type channel in hemi-parkinsonian rats both prevents and reverses LID (Steece-Collier et al, 2019). Cav1.3 has long been appreciated as a key regulator of dendritic spine morphology, including that of MSN, and loss of striatal DA is linked to dysregulation of this channel (Day et al, 2006).…”

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

“…Supporting this idea, in a recent study, a genetic silencing of striatal CaV1.3 voltage‐gated L‐type calcium channels was found to completely prevent LID in severely parkinsonian rats and to ameliorate pre-existing severe LID. 103 …”

“…Supporting this idea, in a recent study, a genetic silencing of striatal CaV1.3 voltage-gated L-type calcium channels was found to completely prevent LID in severely parkinsonian rats and to ameliorate pre-existing severe LID. 103 All the events described in this section (Figure 2) contribute to pathological changes in neuronal firing patterns, which in turn lead to excessive disinhibition of thalamocortical neurons and overactivation of cortical motor areas, and ultimately determine LID development. 17,18…”

Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible

“…In advanced PD, however, symptom control is hampered by the fact that a single dose of medication triggers dyskinesia more easily and lasts for a shorter period of time. Presynaptic mechanisms can explain some features of these motor fluctuations but not their induction by dopamine receptor agonists [3,4].…”