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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, 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.

SUBMITTER: Pearson TS

PROVIDER: S-EPMC8275582 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeDeriving health utilities for rare medical conditions such as aromatic L-amino acid decarboxylase (AADC) deficiency poses challenges. The rarity of AADC deficiency and the fact that this genetic condition often presents in very young children means that robust utility values cannot be derived from the child or their parent/caregiver. Alternative approaches, eg, discrete choice experiments (DCE), are required in order to provide health utilities. The aim of the study was to generate health utilities for AADC deficiency using a DCE.MethodsThe DCE was completed online by panel participants from a UK representative sample. The DCE comprised 6 AADC deficiency attributes (2-6 levels): mobility, muscle weakness, oculogyric crises, feeding ability, cognitive impairment and screaming. These were identified from published literature, clinician input, parent interviews and expert opinion. Participants were presented with 10 choice sets specified using an orthogonal design, including a repeat task to evaluate choice consistency. Participants were presented with 5 health state vignettes prior to the DCE. These were used to elicit time trade-off (TTO) utilities. Multinomial logit models were estimated for the DCE data. The TTO utilities for the worst/best health states were used as anchors to convert indirect DCE part-worth utilities to health utilities.ResultsA total of 1596 participants completed the DCE. The majority (70.7%) gave consistent responses to the repeated choice task; only 1.7% (27) always chose the same alternative for every choice set. Five models were evaluated. There was one preference reversal ("sitting unaided"/"standing with assistance") occurring in all models; these two mobility level coefficients were set to be equal in the final model. Rescaled utilities ranged from 0.494 to 0.7279, corresponding to the worst (633233) and best (111111) health states.ConclusionHealth utilities were derived for AADC deficiency through a DCE. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

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

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