Advancing AADC deficiency therapy through MR-guided multisite delivery of AAV2-hAADC to dopaminergic and serotonergic pathways in the brainstem.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare and often devastating neurometabolic disorder characterized by impaired synthesis of dopamine, serotonin, and norepinephrine. Affected children present with severe developmental delays, motor dysfunction, autonomic instability, and behavioral symptoms, and current treatments remain largely supportive. Current gene therapy trials for AADC deficiency have demonstrated the safety and tolerability of bilateral AAV2-hAADC infusion into the putamen or midbrain. These approaches have restored dopamine synthesis in the basal ganglia and the limbic systems. However, they have not affected serotonin levels, likely due to the lack of transduction of serotonergic neurons by inadequate coverage of relevant brainstem nuclei. Restoring serotonergic signaling may be critical for improving cognitive and behavioral outcomes, which are still not fully addressed by current dopamine-focused therapies. To address this limitation, we evaluated the safety of a multi-target, magnetic resonance (MR)-guided convection-enhanced delivery strategy in nonhuman primates, administering AAV2-AADC into serotonergic and noradrenergic nuclei in addition to current dopaminergic targets. This broader targeting approach aims to enhance serotonin modulation and restore neuromodulatory balance, with potential benefits for cognitive and behavioral function in children with AADC deficiency undergoing gene therapy.