Circuit-specific gene therapy reverses core symptoms in a primate Parkinson’s disease model

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans. [Display omitted] •AAV8R12 efficiently transduces striatal D1-, but not D2-, MSNs after nigral delivery•G88P2/3/7 promoters derived from GPR88 gene induce robust gene expression in MSNs•Systemic ligand infusion selectively activates D1-MSNs after nigral AAV8R12/rM3Ds delivery•Single-dose DCZ rescues PD symptoms in primates for at least 24 h without dyskinesia An AAV-based circuit modulation approach that consists of a designer retrograde AAV capsid, a medium spiny neuron-enriched promoter, and a selected chemogenetic effector specifically modulates direct pathway neurons and rescues parkinsonian symptoms in mouse and macaque Parkinson’s disease models.