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

Area of Science:

• Neuroscience
• Neurology
• Pharmacology

Background:

• Glial cell line-derived neurotrophic factor (GDNF) supports dopamine neuron survival.
• Preclinical studies showed GDNF improved behavioral deficits in animal models of Parkinson's disease.

Purpose of the Study:

• To evaluate the safety, tolerability, and biological activity of GDNF delivered via intracerebroventricular (ICV) catheter in advanced Parkinson's disease (PD).

Main Methods:

• A multicenter, randomized, double-blind, placebo-controlled study involving 50 PD subjects receiving monthly ICV GDNF at escalating doses (25-4,000 microg) for 8 months.
• An open-label extension study provided further exposure up to 20 months.
• Safety, tolerability, and Unified Parkinson's Disease Rating Scale (UPDRS) scores were monitored.

Main Results:

• GDNF did not improve "on" or "off" motor or total UPDRS scores at any dose.
• Adverse events included nausea, anorexia, vomiting, weight loss, paresthesias (Lhermitte sign), and hyponatremia, particularly at higher doses (≥75 microg).
• The open-label extension reported similar adverse events and lack of efficacy.

Conclusions:

• ICV GDNF administration is biologically active, indicated by a range of adverse events.
• GDNF failed to demonstrate therapeutic efficacy in improving parkinsonism.
• Potential reasons for lack of efficacy include inadequate delivery to target brain regions like the putamen and substantia nigra.