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Abstract Details

Intraputaminal AAV-CAv1.3-shRNA Averts Levodopa-induced Dyskinesias and Ameliorates Long-standing Parkinsonian Motor Deficits in Aged Parkinsonian Macaques
Movement Disorders
S26 - Movement Disorders: Basic Science (5:06 PM-5:18 PM)
009

In proof-of-concept studies in parkinsonian rats, we demonstrated that mRNA-level silencing of striatal CaV1.3 channels could prevent induction and significantly reverse established LID, with antidyskinetic benefits maintained into rats of advancing age. Nonhuman primates (NHP) are considered the most accurate model for preclinical studies directed toward impacting human diseases, thus we expanded our studies into aged parkinsonian NHPs.

Identify a novel approach to effectively mitigate levodopa-induced dyskinesias (LID) while maintaining motor benefits of Parkinson disease (PD) therapy (i.e., levodopa).
Male and female Mauritian macaques (24-29 yr. old) received MRI-guided stereotaxic bilateral injections of rAAV-CaV1.3-shRNA or a control rAAV-scrambled (SCR)-shRNA vector eight months after being rendered severely, stably parkinsonian. In these NHP studies, our primary outcome measure was the capacity of AAV-CaV1.3-shRNA to prevent LID induction in subjects exposed to twice-daily (M-Fr) carbidopa:levodopa (25:100 tablets) administered for 5.5 months using a dose escalation paradigm (20, 30, 40mg/kg). Our secondary outcome measures (i.e., PD disability test and fine-motor hand reach task) were to ensure that this therapy did not negatively impact existing motor deficits or benefit of dopamine agonist therapy.
Putaminal CaV1.3 silencing in aged, severely parkinsonian subjects resulted in near complete protection against LID induction (n=4) using a dosage regimen that produced moderate to severe LID in rAAV-SCR-shRNA subjects (n=2). Unexpectedly, this intervention also significantly enhanced motor response to levodopa and reversed long-standing severe motor deficits ‘OFF’ medication.

The therapeutic outcome of robust anti-dyskinetic efficacy together with the motor enhancing benefits, in the presence and absence of levodopa, when scaled up to a NHP model that displays many similarities with human PD, supports the strong promise of targeted (i.e., putaminal) CaV1.3 silencing for continued investigation and potential clinical development.

Authors/Disclosures
Margaret Caulfield (MSU)
PRESENTER
The institution of Dr. Caulfield has received research support from Department of Defense.
Kathy Steece-Collier (Michigan State University) Prof. Steece-Collier has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for RegenxBio. Prof. Steece-Collier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pontifax. The institution of Prof. Steece-Collier has received research support from NIH/NINDS.
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