Can Striatal CaV1.3 Genetic Silencing Prevent Levodopa-Induced Dyskinesias in Parkinson?

Author(s):

New early-stage data suggest that vector‐mediated gene silencing of striatal CaV1.3 expression may hold promise for preventing the induction of levodopa-induced dyskinesias in Parkinson disease.

Kathy Steece‐Collier, PhD, professor, Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University

Kathy Steece‐Collier, PhD

New early-stage data suggest that vector‐mediated gene silencing of striatal CaV1.3 expression may hold promise for preventing the induction of levodopa-induced dyskinesias in Parkinson disease.

Lead author Kathy Steece‐Collier, PhD, professor, Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, and colleagues remarked that these 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 [Parkinson] by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa-induced dyskinesia [adverse] effect.”

Although the treatment is not yet at the in-human stage of testing, results from this animal model showed that in severely parkinsonian rats administered rAAV‐CaV1.3‐shRNA, the suppression of the development of levodopa-induced dyskinesia was significant at Day 1 (P = .013) and from Days 6 through 10 (P <.0026).

In the rats administered the control rAAV‐Scr‐shRNA displayed the typical escalation in levodopa-induced dyskinesia severity over time, which remained both stable and severe as levodopa dose was increased from 6 mg/kg on Day 1 to 10-12 mg/kg and 10-18 mg/kg on Day 6 (Friedman, 39.63; P = .0002; Dunn's post hoc P ≤.0326). Levodopa was administered using a dose‐escalation paradigm beginning 4 weeks postvector administration.

Notably, the prevention of levodopa-induced dyskinesia escalation was maintained, Steece-Collier noted. This was displayed by a near‐absolute disappearance of dyskinetic behavior in the active-group—a significant difference from the control group, beginning on Day 1 of 9 mg/kg levodopa (Kruskal‐Wallis, 159.6; P <.0001; Dunn's post hoc: Scr vs CaV 50 minutes, P = 0.0027; Scr vs CaV 80 minutes, P = 0.0010; Scr vs CaV 110 minutes, P = 0.0109).

“This potent antidyskinetic effect was noted in all rAAV‐CaV‐shRNA parkinsonian rats despite continuing elevation in dose of levodopa over 2 months,” Steece-Collier et al. wrote.

They explained that these studies were consequent from a group of exploratory preclinical studies undertaken to show the novel application of the common antihypertensive dihydropyridine (DHP) drugs for the prevention and/or reversal of levodopa-induced dyskinesias. These studies, unfortunately, revealed partial and transient efficacy but revealed the potential of CaV1.3 channels in Parkinson.

“We hypothesized that if other methods to block CaV1.3 channels were available, this target would provide an optimal anti‐[levodopa-induced dyskinesia] response,” the investigators wrote. “The current study has confirmed this to be true. Using the approach of continuous, high‐potency, target‐specific genetic silencing of striatal CaV1.3 calcium channels with rAAV‐CaV1.3‐shRNA, we have demonstrated that mRNA‐level silencing can provide potent, uniform, and long‐term (>2 months) prevention of LIDs, even with extreme doses of daily levodopa.”

Additionally, they noted that an impossibility with pharmacological CaV silencing—the reversal of preexisting, severe levodopa-induced dyskinesias—was shown to be possible through this methodology. To explore this, the investigators granted a short, 5‐day withdrawal of levodopa to provide an environment in which vector‐mediated reduction might result in a reduction of these dyskinesias.

They observed that on Day 31 postvector (Day 1 following withdrawal) levodopa-induced dyskinesia severity in rAAV‐CaV1.3‐shRNA rats was significantly reduced in comparison with the control rAAV‐Scr‐shRNA group (Day 31: F = 135.7; P <.0001; post hoc Dunn's test, P = .0009).

“Importantly, motor benefit from levodopa was maintained with the knockdown of CaV1.3. We contend that these findings provide some of the strongest preclinical data to date demonstrating the amelioration of LIDs without compromise of motor benefit,” Steece-Collier and colleagues concluded.

REFERENCE

Steece-Collier K, Stancati JA, Collier NJ, et al. Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia. Mov Disord. 2019;34(5):697-707. doi: 10.1002/mds.27695. Published online April 19, 2019.