Gene therapy for Parkinson’s disease models

Parkinson’s disease is a devastating neurodegenerative disorder, characterized by loss of dopaminergic neurons in the midbrain. Treatments such as dopamine receptor agonists or the dopamine precursor levodopa can alleviate some symptoms but this strategy lacks specificity as dopamine receptors are broadly distributed in the brain. Chen et al. developed a gene therapy approach that specifically targets striatal D1 medium spiny neurons (MSNs), which are affected in individuals with Parkinson’s disease. The method uses retrograde adeno-associated virus (AAV8R12) as a delivery vector, promoter sequences derived from the GPR88 gene that are active in D1-MSNs, and a chemogenetic effector that ensures D1-MSN activation after systemic ligand infusion. Application of this strategy to mouse and primate models of Parkinson’s disease was able to rescue locomotion, tremor and other motor skill problems. Although the safety and efficacy of this strategy remains to be tested in human patients and requires further development and assessment (such as the effect on non-motor symptoms), this work indicates that cell-type-specific targeting tools represent an exciting potential therapeutic avenue.

Original reference: Cell 186, 5394–5410.e18 (2023)