Disease-modifying, multidimensional efficacy of putaminal Ca1.3-shRNA gene therapy in aged parkinsonism male and female macaques

Kathy Steece-Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA. Electronic address: collie68@msu.edu.
Margaret E. Caulfield, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Molly J. Vander Werp, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Scott J. Muller, ASU-Banner Neurodegenerative Disease Research Center (NDRC), School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
Jennifer A. Stancati, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Yaping Chu, ASU-Banner Neurodegenerative Disease Research Center (NDRC), School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
Ivette M. Sandoval, Parkinson's Disease Research Unit, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
Timothy J. Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI 49503, USA.
Jeffrey H. Kordower, ASU-Banner Neurodegenerative Disease Research Center (NDRC), School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA.

Document Type

Article

Abstract

There remain several unmet clinical needs in Parkinson's disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. Ca1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against Ca1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-Ca1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-Ca1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-Ca1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD.

Keywords

Ca(V)1.3 channels, Parkinson’s disease, gene therapy, levodopa-induced dyskinesia, motor dysfunction, nonhuman primate

Medical Subject Headings

Animals; Male; Female; Genetic Therapy (methods); Genetic Vectors (genetics, administration & dosage); Dependovirus (genetics); RNA, Small Interfering (genetics); Parkinsonian Disorders (therapy, genetics); Disease Models, Animal; Putamen (metabolism); Humans; Parkinson Disease (therapy, genetics); Magnetic Resonance Imaging; Calcium Channels, L-Type (genetics); RNA Interference

Publication Date

9-3-2025

Publication Title

Molecular therapy : the journal of the American Society of Gene Therapy

E-ISSN

1525-0024

Volume

33

Issue

9

First Page

4338

Last Page

4359

PubMed ID

40437755

Digital Object Identifier (DOI)

10.1016/j.ymthe.2025.05.027

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