Parkinson's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Parkinson's Disease, including details on symptoms, treatment, genetics, medication. | ||||||||
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A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys.Forsayeth JR, Eberling JL, Sanftner LM, Zhen Z, Pivirotto P, Bringas J, Cunningham J, Bankiewicz KS Department of Neurosurgery, University of California at San Francisco, Room MCB 226, 1855 Folsom Street, San Francisco, CA 94103-0555, USA. 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. Published 4 September 2006 in Mol Ther, 14(4): 571-7.
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