title: A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys.
abstract: The main medication for idiopathic Parkinson disease is L-Dopa. Drug efficacy declines steadily in part because the converting enzyme, aromatic L-amino acid decarboxylase (AADC), is lost concomitant with substantia nigra atrophy. Over the past decade, we have developed a gene therapy approach in which AADC activity is restored to the brain by infusion into the striatum of a recombinant adeno-associated virus carrying human AADC cDNA. We report here the results of an investigation of the relationship between vector dose and a series of efficacy markers, such as PET, L-Dopa response, and AADC enzymatic activity. At low doses of vector, no effect of vector was seen on PET or behavioral response. At higher doses, a sharp improvement in both parameters was observed, resulting in an approximate 50% improvement in L-Dopa responsiveness. The relationship between vector dose and AADC enzymatic activity in tissue extracts was linear. We conclude that little behavioral improvement can be seen until AADC activity reaches a level that is no longer rate limiting for conversion of clinical doses of L-Dopa into dopamine or for trapping of the PET tracer FMT. These findings have implications for the design and interpretation of clinical studies of AAV-hAADC gene therapy.
authors.affiliation: Department of Neurosurgery, University of California at San Francisco, Room MCB 226, 1855 Folsom Street, San Francisco, CA 94103-0555, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Forsayeth
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Eberling
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanftner
authors.forename: Zhu
authors.initials: Z
authors.lastname: Zhen
authors.forename: Philip
authors.initials: P
authors.lastname: Pivirotto
authors.forename: John
authors.initials: J
authors.lastname: Bringas
authors.forename: Janet
authors.initials: J
authors.lastname: Cunningham
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D008253:Macaca mulatta; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D049268:Positron-Emission Tomography; D013997:Time Factors
chemical_list: D001142:Aromatic-L-Amino-Acid Decarboxylases