Intraputaminal AAV9 co-delivery of AADC and GDNF in severe AADC deficiency: first-in-human pediatric dose-escalation study.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, severe inherited neurotransmitter disorder causing combined monoamine depletion and severe motor, autonomic, and developmental impairment. Building on established intraputaminal AAV-mediated AADC replacement, we evaluated a next-generation dual-mechanism strategy that couples restoration of dopamine synthesis with neurotrophic circuit support by delivering an AAV9 vector co-expressing human AADC and glial cell line-derived neurotrophic factor (GDNF) in children with genetically confirmed severe AADC deficiency. Four children (36-59 months; 1 female, 3 males) without head control at baseline received a single bilateral MRI-guided intraputaminal infusion at one of three dose levels (2.0×1011, 6.0×1011, or 1.28×1012 vector genomes) and were followed for 52 weeks. The primary endpoint was safety and tolerability. Key secondary outcomes assessed cerebrospinal fluid (CSF) monoamine metabolites, 18F-DOPA PET, motor development, and disease-related symptoms. Treatment was feasible and generally well tolerated, with no vector-related serious adverse events. Biomarker analyses provided convergent evidence of target engagement, including increased CSF metabolites and improved 18F-DOPA uptake, accompanied by improvements in motor function and symptom burden in most participants. By Week 52, one participant achieved full head control and independent sitting, and two achieved partial head control. These first-in-human findings support a dual-gene "enzyme restoration plus circuit support" paradigm and provide a strong translational rationale for further clinical development of this next-generation gene therapy for severe AADC deficiency. ClinicalTrials.gov registration: NCT05765981.