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

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, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

Cognitive Functioning and Academic Performance in Elementary School Children with Anxious/Depressed and Withdrawn Symptoms.

RATIONALE: Few studies have evaluated the relationship between depressive symptomatology and neuropsychological performance in children without symptomatic depression. OBJECTIVES: This study determined the relationship between anxious/depressed and withdrawn symptoms and performance on cognitive and academic achievement measures. METHODS: 335 Caucasian and Hispanic children aged 6 to 11 years who participated in the Tucson Children's Assessment of Sleep Apnea (TuCASA) study were administered a comprehensive neuropsychological battery measuring cognitive functioning and academic achievement. Their parents completed the Child Behavior Checklist (CBCL). Correlations between performance on the cognitive and academic achievement measures and two Internalizing scales from the CBCL were calculated. Comparisons were made between a "Clinical" referral group (using a T-score of ≥ 60 from the CBCL scales) and a "Normal" group, as well as between Caucasians and Hispanics. RESULTS: No differences were found between those participants with increased anxious/depressed or withdrawn symptoms on the CBCL and those without increased symptoms with respect to age, gender, ethnicity, or parental education level. However, significant negative correlations were found between these symptoms and general intellectual function, language, visual construction skills, attention, processing speed, executive functioning abilities, aspects of learning and memory, psychomotor speed and coordination, and basic academic skills. CONCLUSIONS: These findings support the hypothesis that depressive symptomatology negatively impacts performance on cognitive and academic achievement measures in school-aged children and these findings are not affected by ethnicity. The findings also reinforce the concept that the presence of anxious/depressed or withdrawn symptoms needs to be considered when evaluating poor neuropsychological performance in children.