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, 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.
Highlights
Keith Hyland7, Erin Smith8, Gardenia de Oliveira Barbosa9, Jill C
Seven [7] subjects (4 female/3 male, age range 4–9 years, Table 1) were treated with viral gene therapy according to the study protocol
There was some variation in the rate and degree of motor function improvement, 4 of the 5 subjects who had been followed for at least 18 months after gene delivery gained the ability to sit independently, and 2 of the 5 gained the ability to walk with 2-hand support within that time period
Summary
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. Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurodevelopmental disorder that typically presents in infancy, and is characterized biochemically by deficiency of the catecholamines (dopamine, epinephrine, and norepinephrine) and serotonin. Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurodevelopmental disorder that typically presents in infancy, and is characterized biochemically by deficiency of the catecholamines (dopamine, epinephrine, and norepinephrine) and serotonin1 Patients with this condition have been reported in the literature worldwide, though the true incidence is unknown. The rationale for selection of the putamen as the anatomic target in PD for DDC gene therapy is that transduction of the post-synaptic cells that express dopamine receptors in the putamen may provide sufficient AADC activity to cause an increase in local metabolism of exogenous levodopa (i.e., dopaminergic medication) and a subsequent increase in striatal levels of dopamine
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