A Dose-Ranging Study of AAV-hAADC Therapy in Parkinsonian Monkeys

78Citations
Citations of this article
36Readers
Mendeley users who have this article in their library.

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. © 2006.

Cite

CITATION STYLE

APA

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

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free