For the first time, researchers have witnessed dopaminergic neuron sprouting in a Parkinson disease (PD) patient treated with the neurotrophic factor GDNF. A postmortem examination of the brain of a man who showed clinical neurological improvement after receiving GDNF revealed upregulation of the dopaminergic neuron marker tyrosine hydroxylase in the striatum. The results, coming from Stephen Gill’s group in London and published July 3 in Nature Medicine, may provide additional fuel to the fire now raging over the development of GDNF for PD, which was stopped last fall despite protests from clinicians and patients (see ARF related news story).
In the study, first author Seth Love and colleagues examined the brain of a 62-year-old man who had received GDNF infusion into the right posterior putamen for 43 months before the trial was halted, and subsequently died just 3 months later of a heart attack. Over the course of treatment, the man experienced improvement in most measures of neurological functioning and quality of life. Imaging studies during treatment showed increased uptake of labeled dopamine on the infusion side.
Immunostaining of brain sections for tyrosine hydroxylase (TH) revealed fivefold higher levels of the marker in the right (infused) posterior putamen over the left, untreated side. Enhanced TH immunoreactivity was seen up to 10 mm from the tip of the infusion catheter. Most labeling was in a fine, granular pattern, but some larger nerve fibers, axonal swellings, and cell bodies were also labeled. The analysis also revealed a small increase in the axon growth marker Gap43 on the infused side, supporting the idea that neuron sprouting was occurring in the area. Alternatively, existing dysfunctional fibers could have upregulated TH in response to GDNF. “In either case, however, the findings provide a possible substrate for the sustained clinical improvement and enhanced 18F-dopa uptake in humans receiving intraputamenal infusion of GDNF,” the authors write.
The observations reproduced results seen in animal models, which supported the development of GDNF for Parkinson disease in humans. The path has had its twists and turns, however. When promising results from an early, open-label human trial were not replicated in a phase II placebo-controlled design—patients showed no significant difference in neurological outcome between GDNF and placebo after 6 months' treatment—the trial was stopped last fall. Amgen subsequently pulled all patients off the drug for safety reasons, after reporting that high doses of GDNF caused neuron loss in monkeys. Patients who had experienced improvement clamored for the drug and sued Amgen to continue treatment. After a ruling handed down in Amgen’s favor in the US District Court in Manhattan, New York, on June 6, the patients vowed to appeal.—Pat McCaffrey