Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach

Exp Neurol. 2000 Jul;164(1):2-14. doi: 10.1006/exnr.2000.7408.


Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Aromatic-L-Amino-Acid Decarboxylases / genetics
  • Aromatic-L-Amino-Acid Decarboxylases / metabolism
  • Aromatic-L-Amino-Acid Decarboxylases / therapeutic use
  • Carbidopa / therapeutic use
  • Catheterization / methods
  • Caudate Nucleus / diagnostic imaging
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / pathology
  • Cell Line
  • Dependovirus / genetics*
  • Dopamine / metabolism
  • Drug Administration Routes
  • Drug Combinations
  • Fluorine Radioisotopes
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / genetics
  • Genetic Vectors / pharmacokinetics
  • Levodopa / metabolism
  • Levodopa / therapeutic use
  • Macaca mulatta
  • Magnetic Resonance Imaging
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / diagnosis
  • Parkinson Disease, Secondary / genetics*
  • Parkinson Disease, Secondary / therapy*
  • Prodrugs / therapeutic use
  • Putamen / diagnostic imaging
  • Putamen / drug effects
  • Putamen / pathology
  • Tomography, Emission-Computed
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacokinetics
  • Tyrosine 3-Monooxygenase / metabolism


  • Drug Combinations
  • Fluorine Radioisotopes
  • Prodrugs
  • carbidopa, levodopa drug combination
  • 6-fluoro-3-tyrosine
  • Tyrosine
  • Levodopa
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Aromatic-L-Amino-Acid Decarboxylases
  • Carbidopa
  • Dopamine