Direct Delivery of GDNF into the Non-Human Primate and Human Parkinsonian Brain: Success and Road Blocks

R. Grondin, Z. Zhang, Y. Ai, J. Slevint, A. B. Young, D. M. Gash, G. A. Gerhardt

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


Therapeutic strategies for Parkinson's disease (PD) include replacing striatal dopamine using the dopamine precursor levodopa or dopamine receptor agonists, or both. The loss of striatal dopamine and the consequent dysfunction of the nigrostriatal pathway eventually lead to the cardinal symptoms of PD: resting tremor, cogwheel rigidity, bradykinesia, and loss of postural reflex. Novel methods for sustained delivery of glial cell line-derived neurotrophic factor (GDNF) into the nigrostriatal pathway have been studied in non-human primates, including the use of computer-controlled infusion pumps. Using this approach, it has been demonstrated that chronic, intracerebral infusions of GDNF promote restoration of the nigrostriatal dopaminergic system and significantly improve motor functions in rhesus monkeys with neural deficits modeling PD. However, translational studies from the laboratory to the clinic for the treatment of PD have been problematic. On one hand, GDNF was not efficacious when delivered intraventricularly in PD patients, likely failing because of poor drug penetration through the ventricular wall into the parenchyma of the basal ganglia. On the other hand, two independent open label Phase-1 studies have reported marked functional improvements in advanced PD patients receiving chronic intraputamenal infusion of GDNF, whereas a separate, randomized, blinded multicenter trial of intraputmenal GDNF infusion did not achieve the primary study endpoint. In addition, safety concerns have arisen including the presence of neutralizing antibodies to GDNF in some patients. The major difficulty with risk assessment at this time is the failure to have a Phase-2 trial replicating the successful Phase-1 trials in dose and methods of trophic factor delivery. Thus, before any definitive conclusions could be made regarding the use of GDNF as a therapy for PD, a properly designed, adequately powered multicenter Phase-2 clinical trial should be conducted in PD patients.

Original languageEnglish
Title of host publicationCNS Regeneration
Subtitle of host publicationBasic Science and Clinical Advances
Number of pages22
StatePublished - Dec 27 2007

Bibliographical note

Publisher Copyright:
© 2008 Elsevier Inc. All rights reserved.

ASJC Scopus subject areas

  • General Neuroscience


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