Enhancer-based AAV approach for selective AADC delivery reduces motor symptoms and dyskinesia in Parkinson’s mouse models

Profound degeneration of dopamine (DA) neurons and reduced DA levels in the brain is recognized as an underlying cause of Parkinson’s Disease (PD). The standard treatment for PD is levodopa (L-DOPA), but its effectiveness wanes over time and prolonged usage can lead to L-DOPA-induced-dyskinesia (LID). An adeno-associated virus (AAV)-based strategy to overexpress aromatic l-amino acid decarboxylase (AADC) in the striatum combined with L-DOPA therapy shows promise for symptomatic improvement but requires an invasive delivery approach. Here, we generated enhancer AAVs to drive AADC expression in key cell types and paired them with a blood-brain barrier (BBB)-penetrant capsid. We characterized the AAVs in mouse following multiple routes of administration and found that cell-type specific viral treatment ameliorated motor deficits and LID in PD disease models. This cell type-specific viral rescue strategy showed similar or better phenotypic rescue compared to a ubiquitous targeting approach and improved mortality. Additionally, we characterized the expression of an AAV-AADC vector capable of mouse phenotypic rescue in non-human primate (NHP) following two routes of administration. This novel therapeutic strategy in combination with L-DOPA may enable a less invasive and better tolerated approach to treat motor deficits in PD patients.