title: SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE.
abstract: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in theDDCgene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of non-human primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3 or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Waldy
authors.initials: W
authors.lastname: San Sebastian
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bringas
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Lluis
authors.initials: L
authors.lastname: Samaranch
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ciesielska
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Macayan
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Pivirotto
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.affiliation: Consultant.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Osborne
authors.affiliation: Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA ; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Foad
authors.initials: F
authors.lastname: Green
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Heller
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
keywords: AADC deficiency; AAV2-hAADC; MRI-guided; pressurized infusion