Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys

Hum Gene Ther. 2009 Dec;20(12):1627-40. doi: 10.1089/hum.2009.103.


We evaluated neuropathological findings in two studies of AAV2-GDNF efficacy and safety in naive aged (>20 years) or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus macaques. In the first study, a total of 17 animals received one of two doses of AAV2-GDNF into either putamen or substantia nigra (SN). To control for surgical variables, all animals received identical putaminal and nigral infusions in which phosphate-buffered saline was substituted for vector as appropriate. All 17 aged monkeys were studied for 6 months before necropsy. In a separate study, 11 MPTP-lesioned rhesus macaques with extensive lesions in the right SN and mild lesions in the left SN received bilateral infusions of AAV2-GDNF (9.9 x 10(11) vector genomes) or PBS into the putamen and were then studied for up to 14 months. In the current analysis, we addressed safety issues regarding AAV2-GDNF administration. An extensive series of assessments of in-life behavioral and clinical parameters was conducted. No overt histopathology or immune responses were detected in any experimental monkey. However, the delivery of AAV2-GDNF to the SN of aged monkeys caused a marked and significant loss of body weight (-19.4%). No weight loss was observed in the MPTP-lesioned monkeys despite bilateral axonal transport of glial cell line-derived neurotrophic factor (GDNF) to the SN from the putamen. These findings indicate that putaminal administration of AAV2-GDNF by convection-enhanced delivery shows therapeutic promise without any apparent side effects. Importantly, nigral administration of AAV2-GDNF caused significant weight loss that raises substantial concern for clinical application of this approach.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Adenoviridae / genetics
  • Adenoviridae / immunology
  • Age Factors
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopamine Agents / pharmacology
  • Gene Transfer Techniques / adverse effects*
  • Genetic Therapy*
  • Glial Cell Line-Derived Neurotrophic Factor / genetics*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Humans
  • Macaca mulatta
  • Parkinson Disease / pathology
  • Parkinson Disease / therapy*
  • Parkinson Disease, Secondary / pathology
  • Parkinson Disease, Secondary / therapy*
  • Substantia Nigra / metabolism*


  • Dopamine Agents
  • Glial Cell Line-Derived Neurotrophic Factor
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Dopamine