Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Neurology. 2003 Jan 14;60(1):69-73. doi: 10.1212/wnl.60.1.69.


Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD.

Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys.

Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies.

Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy.

Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anorexia / etiology
  • Cohort Studies
  • Diarrhea / etiology
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor
  • Humans
  • Hyponatremia / etiology
  • Injections, Intraventricular
  • Male
  • Middle Aged
  • Nausea / etiology
  • Nerve Growth Factors / administration & dosage
  • Nerve Growth Factors / adverse effects
  • Nerve Growth Factors / therapeutic use*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / therapeutic use*
  • Paresthesia / etiology
  • Parkinson Disease / drug therapy*
  • Treatment Failure
  • Vomiting / etiology
  • Weight Loss


  • GDNF protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Neuroprotective Agents