A Novel Treatment for Parkinson’s Disease With Remarkable Results 

Abstract & Commentary 

Source: Gill SS, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nature Medicine advance online publication. www.nature.com.

A number of neurotrophic factors have great promise for the treatment of neurologic diseases. Prior work showed that a number of neurotrophic factors appeared to have promise for treating ALS, as well as peripheral neuropathy. Unfortunately, the initial trials with several factors failed in ALS, and a trial of nerve growth factor in diabetic neuropathy also was unsuccessful. The present trial describes the effects of glial cell-line derived neurotrophic factor (GDNF) in 5 Parkinson’s patients. The rational for examining glial neurotrophic factor is that it is one of the most potent growth factors that supports dopaminergic neurons. A large body of preclinical evidence had demonstrated that glial-derived neurotrophic factor will exert both neuroprotective effects, as well as neurorestorative effects, in animal models of Parkinson’s disease. Neuro-restoration refers to regrowth of dopaminergic terminals, thereby restoring function by enhancing the function of the residual neurons. GDNF has been previously administered both in rodents and primates. In particular, a trial studying the effects of lentivirusdelivered GDNF showed marked neuroprotective effects in the model of Parkinson’s disease in primates.

A previous trial used GDNF administered intraventricularly in Parkinson’s disease patients; it was unsuccessful. Patients also had significant side effects, and there was no evidence of restoration of dopamine fibers in the striatum in 1 subject studied post-mortem. It was theorized that this lack of efficacy was because of an insufficient concentration of GDNF reaching the relevant structures. In the present study, the direct effects of infusion of GDNF into the putamen of 5 Parkinson’s patients was therefore studied in a phase 1 safety trial. Gill and associates demonstrate remarkable improvement. The drug was infused by means of a catheter localized to the dorsal lateral putamen, which is the site that shows the greatest loss of dopaminergic fibers in Parkinson’s disease. In several patients there was increased T2 signal around the tip of the catheter. This was dissipated following a reduction in the infusion rate. There were no other serious side effects. There was no nausea, anorexia, vomiting, or weight loss, which had been seen in the previous intraventricular trial. The only consistent side effect was Lhermitte’s phenomenon, consisting of tingling passing from the neck down to the arms and sometimes to the trunk.

The patients were examined at 3, 6, and 12 months after the infusions. Periods of severe immobility that had occupied approximately 20% of the waking day before surgery were eliminated completely after 6 months of GDNF infusion. The overall improvement of the UPDRS scale, a widely used and validated scale for assessing functional changes in Parkinson’s disease, showed a 39% improvement in the motor subscore after 1 year. There was a 61% improvement in the activities of daily living subscore. The improvement persisted throughout the trial. Another remarkable effect in the trial was that dyskinesias improved markedly in 4 patients. There were no increases in dyskinesias in the patients when they were off medication, which contrasts with the fetal transplant studies. Timed motor tests were improved in both the off- and on-medication states. An unexplained finding was an improvement in smell and taste. There were no effects on cognitive function. Gill et al also examined [18F]dopamine PET scan changes. They observed that immediately surrounding the catheter there was a 28% increase in putamen dopamine storage after 18 months, whereas in the remaining putamen there was a continuing decline in dopamine.


This is an extraordinary report and extremely exciting finding. The results in such a small number of patients are phenomenally good. It suggests that GDNF may have neuroprotective and neurorestorative effects in Parkinson’s disease patients. This raises the possibility that this type of strategy may be applicable to other neurodegenerative diseases. It is also possible that GDNF or other growth factors could be administered by gene therapy or by transplantation of neural-stem cells secreting GDNF. In fact, one of the authors is presently evaluating this strategy. In summary, this is one of the most exciting recent reports on potential novel treatments for an otherwise inexorably progressive neurodegenerative illness. — M. Flint Beal

Dr. Beal is Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY