Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats

Mol Ther. 2001 Oct;4(4):324-30. doi: 10.1006/mthe.2001.0466.

Abstract

In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.

MeSH terms

  • Animals
  • Apomorphine / pharmacology
  • Aromatic-L-Amino-Acid Decarboxylases / genetics*
  • Aromatic-L-Amino-Acid Decarboxylases / metabolism
  • Aromatic-L-Amino-Acid Decarboxylases / therapeutic use*
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Dopamine / metabolism
  • Gene Transfer Techniques*
  • Genetic Therapy / methods
  • Genetic Vectors / genetics
  • Levodopa / chemistry
  • Levodopa / metabolism
  • Levodopa / pharmacology
  • Neostriatum / drug effects
  • Neostriatum / enzymology
  • Neostriatum / metabolism*
  • Neostriatum / pathology
  • Oxidopamine / pharmacology
  • Parkinson Disease / genetics*
  • Parkinson Disease / physiopathology
  • Parkinson Disease / therapy*
  • Parkinson Disease, Secondary / chemically induced
  • Rats
  • Rats, Sprague-Dawley
  • Rotation
  • Transduction, Genetic

Substances

  • Levodopa
  • Oxidopamine
  • Aromatic-L-Amino-Acid Decarboxylases
  • Apomorphine
  • Dopamine