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. © 2006.
Forsayeth, J. R., Eberling, J. L., Sanftner, L. M., Zhen, Z., Pivirotto, P., Bringas, J., … Bankiewicz, K. S. (2006). A Dose-Ranging Study of AAV-hAADC Therapy in Parkinsonian Monkeys. Molecular Therapy, 14(4), 571–577. https://doi.org/10.1016/j.ymthe.2006.04.008