GDNF Shows Potential as Neurorestorative Treatment for Parkinson’s

Infusion of a naturally occurring protein, GDNF, into a motor control area of the brain may restore cells damaged by Parkinson’s disease and ease patients’ symptoms, results from a European clinical trial suggest.

The study, “Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Evidence shows that glial cell line-derived neurotrophic factor (GDNF) supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease. In animal models of Parkinson’s, GDNF has consistently demonstrated both neuroprotective and neurodegenerative effects when provided continuously.

Researchers developed a three-part clinical trial (EudraCT Number: 2013-001881-40) to study the safety and effectiveness of GDNF infusions in Parkinson’s patients. The trial first recruited six patients to assess the safety of the treatment. Then, 35 more participants entered the nine-month, double blind trial in which half were given monthly infusions of GDNF. The other half received placebo infusions through an implant that delivered the treatment directly to the brain through a port placed behind the ear.

This part of the study showed that patients who received monthly doses of GDNF into their putamen — a brain region involved in movement control that’s deeply damaged in Parkinson’s — had a significant increase of dopamine levels in the brain compared to the placebo group. However, the apparent increase in dopamine levels were not reflected on patients’ clinical status.

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“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” principal investigator Alan L. Whone, PhD, said in a press release. Whone is in Translational Health Sciences, Bristol Medical School, University of Bristol, and Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK,  “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s,” he said.

Using the same patient sample (41 subjects, ages 35–75) researchers further assessed the effects of continued (21 patients who had received GDNF) or new (20 patients who had received placebo) exposure to GDNF for another nine months in the open-label extension phase of the trial. Dosing followed the same protocol as before with GDNF infusion given every month.

Although all patients knew they were receiving GDNF, they remained oblivious to what their treatment in the previous study was.

The primary goal of the study was measure the percentage change from parent trial week zero to week 80 (or week 40, depending on the study group) in the “off” state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. As disease progresses, patients experience off periods more frequently. Such episodes are characterized by the reappearance or worsening of symptoms due to diminishing effects of levodopa therapy.

The treatment had no treatment-emergent safety issues, but all patients experienced at least one adverse side effect, including application site infection, headache, back pain, and uncontrollable muscle contraction (dystonia).

By 18 months (all participants had received GDNF), both groups showed a trend toward score reduction, indicating motor function improvement. GDNF also was found safe when administered over this length of time. However, there were no significant differences in off state UPDRS motor score between patients who received GDNF for 18 months and those who received it for nine months only (parent study placebo group).

Importantly, total off time and good-quality “on” time per day improved in both study groups.

In comparison to the beginning of the parent trial, mean total off time per day decreased by an average of 1.5 hours in patients who received GDNF throughout the whole study, and by 0.8 hours in the those who received placebo and GDNF. “Good-quality ON time increased by [an average of 1.6] hours in the GDNF/GDNF group and by [0.5] hours in the placebo/GDNF group,” researchers wrote.

“This trial has shown that we can safely and repeatedly infuse drugs directly into patients’ brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson’s, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier,” said senior author Steven Gill, honorary professor in neurosurgery at the University of Bristol, and designer of the GDNF delivery system (Convection Enhanced Delivery, CED).

“I believe that this approach could be the first neurorestorative treatment for people living with Parkinson’s, which is, of course, an extremely exciting prospect,” Gill stated.