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

Toni S. Pearson, Nalin Gupta, Waldy San Sebastian, Jill Imamura-Ching, Amy Viehoever, Ana Grijalvo-Perez, Alex J. Fay, Neha Seth, Shannon M. Lundy, Youngho Seo, Miguel Pampaloni, Keith Hyland, Erin Smith, Gardenia Barbosa, Jill C. Heathcock, Amy Minnema, Russell Lonser, J. Bradley Elder, Jeffrey Leonard, Paul Larson and Krystof S. Bankiewicz ()
Additional contact information
Toni S. Pearson: University of California San Francisco
Nalin Gupta: University of California San Francisco
Waldy San Sebastian: University of California San Francisco
Jill Imamura-Ching: University of California San Francisco
Amy Viehoever: University of California San Francisco
Ana Grijalvo-Perez: University of California San Francisco
Alex J. Fay: University of California San Francisco
Neha Seth: University of California San Francisco
Shannon M. Lundy: University of California San Francisco
Youngho Seo: University of California San Francisco
Miguel Pampaloni: University of California San Francisco
Keith Hyland: Medical Neurogenetics Laboratories
Erin Smith: Therapy Services, St. Louis Children’s Hospital
Gardenia Barbosa: The Ohio State University
Jill C. Heathcock: The Ohio State University
Amy Minnema: The Ohio State University
Russell Lonser: The Ohio State University
J. Bradley Elder: The Ohio State University
Jeffrey Leonard: The Ohio State University
Paul Larson: University of California San Francisco
Krystof S. Bankiewicz: University of California San Francisco

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24524-8

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