A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys

Mol Ther. 2006 Oct;14(4):571-7. doi: 10.1016/j.ymthe.2006.04.008. Epub 2006 Jun 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatic-L-Amino-Acid Decarboxylases / genetics
  • Aromatic-L-Amino-Acid Decarboxylases / metabolism*
  • Behavior, Animal
  • Dependovirus / genetics*
  • Genetic Therapy*
  • Humans
  • Macaca mulatta
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics*
  • Parkinson Disease / therapy*
  • Positron-Emission Tomography
  • Time Factors


  • Aromatic-L-Amino-Acid Decarboxylases