Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal.

Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated. During the extended study period, patients received a 30-microg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 microl/hour. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing. The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.