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From Oregon Health & Science University (Drs. Nutt and Burchiel), Portland; Rush Presbyterian St. Luke’s Medical Center (Drs. Comella and Penn), Chicago, IL; Baylor College of Medicine (Drs. Jankovic and Simpson), Houston, TX; Toronto Western Hospital (Drs. Lang and Lozano), Canada; Department of Neurology (Drs. Laws and Wooten), University of Virginia Health Sciences Center, Charlottesville; and Barrows Neurological Institute (Dr. Stacy), Phoenix, AZ.
Address correspondence and reprint requests to Dr. J.G. Nutt, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, OP32, Portland, OR 97201-3098; e-mail: nuttj{at}ohsu.edu
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 µg 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 µg 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 µg 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 µg 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.
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