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.

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Background: 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.Objective: We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency. Design, Setting and Participants: 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 x 1011 vg (n=3), and 4.2 x 1011 vg (n=4). Six (6) subjects were treated at UCSF Benioff Children’s Hospital in San Francisco and 1 at The Ohio State University.Results: Direct bilateral infusion of AAV2-hAADC was 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. Eighteen (18) months after surgery (n=5), 4/5 subjects gained the ability to sit independently and 2/5 could walk with 2-hand support.Conclusion: Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to substantial clinical improvements in symptoms and motor function.Trial Registration: ClinicalTrials.gov Identifier NCT02852213

Objectives: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized by infiltration of eosinophils into the esophagus. Primary treatment approaches include topical corticosteroids and/or food elimination. The aim of the present study was to compare the effectiveness of combination therapy (topical corticosteroid plus test-based food elimination [FS]) with single therapy (topical corticosteroid [S] or test-based food elimination [F]). Methods: Chart review of patients with EoE at Texas Children's Hospital (age <21 years) was performed. Clinical and histological statuses were evaluated after a 3-month treatment with either single or combination therapy. Comparisons were analyzed using Fisher exact test, Kruskal-Wallis tests, and multiple logistic regression models. Results: Among 670 charts, 63 patients (1-21 years, median 10.3 years) with clinicopathologic diagnoses of EoE were identified. Combination FS therapy was provided to 51% (n ¼ 32) and single treatment (S, F) to 27% (n ¼ 17) or 22% (n ¼ 14) of patients, respectively. Clinical responses were noted in 91% (n ¼ 29), 71% (n ¼ 12), and 64% (n ¼ 14) of patients in the FS, S, and F groups, respectively. The odds of clinically improving were 4.6 times greater (95% confidence interval: 1.1-18.8) with combination versus single therapy. The median peak number of eosinophils per high-power field after 3-month therapy was not significantly different in the S, F, and FS groups. Conclusions: The combination of topical corticosteroids with specific food elimination is as effective in achieving clinical and histological remissions as the single-treatment approaches. Responses were achieved with the combination in patients who had previously failed single-agent therapy. Prospective research of this combination approach in young patients with EoE is needed.