Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons

Abstract Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, causes severe developmental disability lifelong motor, behavioral, autonomic symptoms including oculogyric crises (OGC), sleep disorder, mood disturbance. We investigated the safety efficacy delivery viral vector expressing AADC (AAV2-hAADC) to midbrain children with (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced (CED) AAV2-hAADC bilateral substantia nigra (SN) ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) 2 dose cohorts: 1.3 × 10 11 vg (n = 3), 4.2 4). Primary aims were demonstrate procedure document biomarker evidence restoration brain activity. Secondary assess clinical improvement motor function. Direct was safe, well-tolerated achieved target coverage 98% 70% SN VTA, respectively. Dopamine metabolism increased all subjects FDOPA uptake enhanced within striatum. OGC resolved completely 6 7 Month 3 post-surgery. Twelve (12) months after surgery, 6/7 gained normal head control 4/7 could sit independently. At 18 months, walk 2-hand support. Both primary secondary endpoints study met. Midbrain gene feasible leads improvements