Objective: To determine whether striatal CaV1.3 gene silencing ameliorates levodopa-induced dyskinesias (LID) in the preclinical gold-standard non-human primate (NHP) model without altering levodopa’s antiparkinsonian benefit.

Background: We previously reported that mRNA-level silencing of striatal CaV1.3 channels in young adult male parkinsonian rats prior to the introduction of levodopa could completely prevent LID induction even with prolonged dose escalation¹. To advance our understanding of the potential clinical utility of this gene therapy approach, we are undertaking a second phase of investigations examining the ability of striatal CaV1.3 silencing to impact LID development in aged male and female parkinsonian macaques.

Method: Male and female Mauritian cynomolgous monkeys (23-24 yrs) received a unilateral intracarotid injection of the neurotoxin MPTP to induce unilateral parkinsonism. Two weeks later they began receiving intravenous MPTP injections (0.3-0.6 mg/kg) until significant bilateral parkinsonian motor signs appeared (~3mo). Cumulative stabilization of PD motor impairments occurred over ~8 mos (prolonged due to pandemic) prior to bilateral putaminal injections of AAV-CaV1.3-shRNA designed against primate/macaque CaV1.3 (N=2 male; N=2 female), or AAV-Scr-shRNA (N=1 male). A second cohort of N=2 Scr-shRNA, N=1 CaV-shRNA is ongoing. Levodopa:carbidopa (25:100; p.o., b.i.d., M-Fr) was administered at escalating doses (20mg/kg for 3.5mo; 30mg/kg for 1mo; 40mg/kg for 1mo). PD disability (PDD) ‘ON’ & ‘OFF’ levodopa, hand-reach task and LID were evaluated at regular intervals.

Results: LID was first observed post-vector (PV) wk16 on day 43 of 20mg/kg (peak dose LID severity scores: Scr=12.0; CaV=1.0+0.35, mean+SEM). LID severity continued to escalate in the Scr-shRNA subject but remained equally negligible in all CaV-shRNA subjects (peak LID severity, final day of 40mg/kg: Scr=29.0; CaV=2.8+0.65). This anti-dyskinogenic effect occurred in the presence of levodopa-induced rotations and decrease in cumulative PDD (Wks7-28 PV) ‘ON’ & ‘OFF’ levodopa (p<0.01-0.001, Freidman’s test & Dunn’s post-hoc).

Conclusion: Decreasing striatal expression of CaV1.3 in aged male & female NHPs can provide near complete protection against LID induction when gene therapy is administered to NHP with long-standing severe parkinsonian disability and prior to introduction of levodopa.

References: [1] Steece-Collier K, Stancati JA, Collier NJ, Sandoval IM, Mercado NM, Sortwell CE, Collier TJ, Manfredsson FP. Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia. Mov Disord. (2019) 34(5):697-707. PMID: 31002755

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MDS Abstracts - https://www.mdsabstracts.org/abstract/antidyskinetic-effects-of-cav1-3-calcium-channel-gene-silencing-in-aged-male-and-female-parkinsonian-macaques/