Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF

J Neurosci. 2010 Jul 14;30(28):9567-77. doi: 10.1523/JNEUROSCI.0942-10.2010.


Clinical studies to date have failed to establish therapeutic benefit of glial cell-derived neurotrophic factor (GDNF) in Parkinson's disease (PD). In contrast to previous nonclinical neuroprotective reports, this study shows clinically relevant and long-lasting regeneration of the dopaminergic system in rhesus macaques lesioned with 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine 3-6 months before GDNF gene delivery (AAV2-GDNF). The observed progressive amelioration of functional deficits, recovery of dopamine, and regrowth of fibers to the striatal neuropil demonstrate that high GDNF expression in the putamen promotes restoration of the dopaminergic system in a primate model of advanced PD. Extensive distribution of GDNF within the putamen and transport to the severely lesioned substantia nigra, after convection-enhanced delivery of AAV2-GDNF into the putamen, indicates anterograde transport via striatonigral connections and is anticipated to occur in PD patients. Overall, these data demonstrate nonclinical neurorestoration after putaminal infusion of AAV2-GDNF and suggest that clinical investigation in PD patients is warranted.

Publication types

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

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Analysis of Variance
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Chromatography, High Pressure Liquid
  • Dopamine / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / therapeutic use*
  • Immunohistochemistry
  • Macaca mulatta
  • Male
  • Nerve Regeneration / genetics*
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Parkinsonian Disorders / therapy*
  • Recovery of Function


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